Novel process for the synthesis of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1eta-pyrrole-3-carboxylic acid phenylamide

ABSTRACT

An improved process for the preparation of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide by a novel synthesis is described where methyl cyanoacetate is converted in eight operations or fewer to the desired product, as well as other valuable intermediates used in the process.

FIELD OF THE INVENTION

An improved synthesis for the preparation of5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide is described where methyl cyanoacetate is converted ineight operations or fewer to the desired product, as well as othervaluable intermediates used in the process.

BACKGROUND OF THE INVENTION

5-(4-Fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide is a valuable intermediate in the synthesis of Lipitor®(atorvastatin calcium) known by the chemical name[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1) trihydrate. The aforementioned compound isuseful as an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMG-COA reductase) and is thus useful as a hypolipidemicand/or hypocholesterolemic agent.

U.S. Pat. No. 4,681,893, which is herein incorporated by reference,discloses certain trans-6-[2-(3- or4-carboxamido-substituted-pyrrol-1-yl)alkyl]-4-hydroxy-pyran-2-onesincluding trans (O)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-](2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.

U.S. Pat. No. 5,273,995, which is herein incorporated by reference,discloses the enantiomer having the (R,R) form of the ring-opened acidof trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide,i.e.,[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid.

U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837;5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792;5,342,952; 5,298,627; 5,446,054; 5,470,981; 5,489,690; 5,489,691;5,510,488; 5,998,633; and 6,087,511, which are herein incorporated byreference, disclose various processes and key intermediates forpreparing atorvastatin.

Crystalline forms of atorvastatin calcium are disclosed in U.S. Pat.Nos. 5,969,156 and 6,121,461 which are herein incorporated by reference.

A synthetic procedure for the preparation of5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide is disclosed in U.S. Pat. No. 5,273,995.

The asymmetric reduction of β-ketoesters, as well as β-diketones, is awell-established transformation in organic synthesis. However, thecomplexity of these reactions increases in the case of 1,3,5-tricarbonylsystems and poor yields and poor stereoselectivities often result. Infact, investigations by Saburi (Tetrahedron, 1997, 1993;49) andCarpentier (Eur. J. Org. Chem. 1999;3421) have independentlydemonstrated low to moderate diastereo- and/or enantio-selectivities fordiketoester asymmetric hydrogenations. Furthermore, the fact that theprocesses in the prior art require high pressure hydrogenation andextended reaction times makes these procedures impractical and notamenable to large-scale manufacturing processes.

However, we have surprisingly and unexpectedly found that the diolesters of the present invention,(R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoicacid esters, can be obtained directly from the corresponding1,3,5-tricarbonyl precursors in a highly stereoselective manner via amild and efficient ruthenium-catalyzed asymmetric hydrogenation reactionutilizing chiral non-racemic diphosphine ligands in the presence ofsecondary activating agents such as protic acids.

The object of the present invention is a short and efficient process forthe preparation of5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide. The present process avoids the use of a costly chiralraw material ((R)-4-cyano-3-hydroxy-butyric acid ethyl ester), and a lowtemperature diastereoselective borane reduction. Furthermore, a keyPaal-Knorr condensation step, common to the present and prior artprocesses, has been improved through a significant decrease in reactiontime.

Thus, the present process has significant advantages over the prior artprocesses and is amenable to large-scale synthesis.

SUMMARY OF THE INVENTION

Accordingly, the first aspect of the present invention is an improvedprocess for the preparation of a compound of Formula (13)

-   -   which comprises:    -   Step (a) reacting a compound of Formula (1)    -   wherein R is alkyl, aryl, arylalkyl, or heteroaryl in a solvent        with a compound of Formula (2)        R¹—H  (2)    -   wherein R¹ is —XR wherein        -   X is O,        -   S, or        -   Se, or R¹ is    -   wherein R² or R³ is independently        -   R³        -   alkyl,        -   cycloalkyl,        -   arylalkyl, or        -   aryl, or        -   R² and R³ together are        -   —(CH₂)₄—,        -   —(CH₂)₅—,        -   —(CH(R⁴)—CH₂)₃—,        -   —(CH(R⁴)—CH₂)₄—,        -   —(CH(R⁴)—(CH₂)₂—CH(R⁴))—,        -   —(CH(R⁴)—(CH₂)₃—CH(R⁴))—,        -   —CH₂—CH₂-A-CH₂—CH₂—,        -   —CH(R⁴)—CH₂-A-CH₂CH₂—,        -   —CH(R⁴)—CH₂-A-CH₂—CH(R⁴)—    -   wherein R⁴ is alkyl of from one to four carbon atoms, A is O, S,        or N and R is as defined above to afford a compound of Formula        (3)    -   wherein R¹ is as defined above;    -   Step (b) reacting a compound of Formula (3) with hydrogen in the        presence of a catalyst and a strong acid in a solvent to afford        a compound of Formula (4)    -   wherein Y is Cl, Br, TsO, MsO, or HSO₄, and R¹ is as defined        above;    -   Step (c) reacting a compound of Formula (4) with a base in a        solvent followed by the addition of a compound of Formula (5)        R—CO₂H  (5)    -   wherein R is as defined above in a solvent to afford a compound        of Formula (6)    -   wherein R and R¹ are as defined above;    -   Step (d) reacting a compound of Formula (6) with Compound (7)    -   in a solvent with removal of water to afford a compound of        Formula (8)    -   wherein R¹ is as defined above;    -   Step (e) reacting a compound of Formula (8) with a compound of        Formula (9)    -   wherein M is sodium, lithium, potassium, zinc, magnesium,        copper, calcium, or aluminum and R¹ is as defined above, in a        solvent in the presence of a strong base to afford a compound of        Formula (10)    -   wherein R¹ is as defined above;    -   Step (f) reacting a compound of Formula (10) with hydrogen in        the presence of a catalyst in a solvent in the presence of an        acid to afford a compound of Formula (11)    -   wherein R¹ is as defined above or a compound of Formula (11a)    -   Step (g) reacting a compound of Formula (11b)    -   wherein R^(1a) is OH, —XR wherein        -   X is O,        -   S, or        -   Se, or R^(1a) is    -   wherein R² or R³ is independently        -   alkyl,        -   cycloalkyl,        -   arylalkyl, or        -   aryl, or        -   R² and R³ together are        -   —(CH₂)₄—,        -   —(CH₂)₅—,        -   —(CH(R⁴)—CH₂)₃—,        -   —(CH(R⁴)—CH₂)₄—,        -   —(CH(R⁴)—(CH₂)₂—CH(R⁴))—,        -   —(CH(R⁴)—(CH₂)₃—CH(R⁴))—,        -   —CH₂—CH₂-A-CH₂—CH₂—,        -   —CH(R⁴)—CH₂-A-CH₂CH₂—,        -   —CH(R⁴)—CH₂-A-CH₂—CH(R⁴)—    -   wherein R⁴ is alkyl of from one to four carbon atoms, A is O, S,        or N, and R is as defined above in a solvent in the presence of        an acid, followed by reaction with a base, an acylating agent,        and an acylation catalyst in a solvent to afford a compound of        Formula (12)    -   Step (h) reacting a compound of Formula (12) with HO-M in an        alcohol of Formula (17) or (17b)        HOCH₂-Aryl (17) or HO-Allyl (17b)    -   wherein M is sodium, lithium, potassium, zinc, magnesium,        copper, calcium, or aluminum; or with a compound of Formula (16)        or (16b)        M^({circle over (+)} {circle over (−)}) OCH₂-Aryl (16) or        M^({circle over (+)} {circle over (−)}) O-Allyl  (16b)    -   wherein M is as defined above in an alcohol of Formula (17) or        (17b) wherein aryl or allyl in a compound of Formula (16) or        (16b) and (17) or (17b) is the same, in a solvent followed by        the addition of hydrogen in the presence of a catalyst and an        acid to afford the compound of Formula (13).

A second aspect of the present invention is an improved process for thepreparation of a compound of Formula (8).

-   -   wherein R¹ is as defined above which comprises:    -   reacting a compound of Formula (4)    -   wherein Y is Cl, Br, TsO, MsO, or HSO₄, and R¹ is as defined        above with a compound of Formula (20)        R—CO₂ ^({circle over (−)} {circle over (+)}) M  (20)    -   wherein R and M are as defined above with Compound (7)    -   in a solvent with removal of water to afford a compound of        Formula (8).

A third aspect of the present invention is an improved process for thepreparation of compound (13)

-   -   which comprises:    -   Step (a) reacting a compound of Formula (11) with an acetal of        Formula (15)    -   wherein R⁵ and R⁵a are independently the same or different and        are, methyl, ethyl, or —(CH₂)_(n)— wherein n is an integer of 2        to 4, and R is as defined above in a solvent in the presence of        an acid followed by the addition of an aldehyde corresponding to        the previous acetal in the presence of a base to afford a        compound of Formula (14)    -   wherein R¹ and R are as defined above;    -   Step (b) reacting a compound of Formula (14) in a nucleophilic        solvent in the presence of an acid or optionally reaction with        hydrogen in the presence of a catalyst and an acid in a solvent        to afford the compound of Formula (13); and    -   Step (c) alternatively, reacting a compound of Formula (11) or        (1 la) in a non-nucleophilic solvent in the presence of an acid        to afford a compound of Formula (13).

A fourth aspect of the present invention is a process for thepreparation of a compound of Formula (1 lb)

-   -   wherein R^(1a) is OH, —XR wherein        -   X is O,        -   S, or        -   Se, or R^(1a) is    -   wherein R² or R³ is independently        -   alkyl,        -   cycloalkyl,        -   arylalkyl, or        -   aryl, or        -   R² and R³ together are        -   —(CH₂)₄—,        -   —(CH₂)₅—,        -   —(CH(R⁴)—CH₂)₃—,        -   —(CH(R⁴)—CH₂)₄—,        -   —(CH(R⁴)—(CH₂)₂—CH(R⁴))—,        -   —(CH(R⁴)—(CH₂)₃—CH(R⁴))—,        -   —CH₂—CH₂-A-CH₂—CH₂—,        -   —CH(R⁴)—CH₂-A-CH₂CH₂—,        -   —CH(R⁴)—CH₂-A-CH₂—CH(R⁴)—    -   wherein R⁴ is alkyl of from one to four carbon atoms, A is O, S,        or N, and R is alkyl, aryl, arylalkyl, or heteroaryl which        comprises:    -   Step (a) reacting a compound of Formula (10)    -   wherein R¹ is as defined above with one mole of hydrogen in the        presence of a catalyst in a solvent in the presence of an acid        to afford compounds of Formula (18) and/or Formula (18a)    -   wherein R¹ is as defined above; and    -   Step (b) reacting either a compound of Formula (18) or (18a)        with hydrogen in the presence of a catalyst in a solvent in the        presence of an acid to afford a compound of Formula (11b).

A fifth aspect of the present invention is a compound of Formula (6)

-   -   wherein R is alkyl, aryl, arylalkyl, or heteroaryl, and    -   R¹ is XR wherein        -   X is O,        -   S, or        -   Se, or R¹ is    -   wherein R² or R³ is independently        -   alkyl,        -   cycloalkyl,        -   arylalkyl, or        -   aryl or        -   R² and R³ together are        -   —(CH₂)₄—,        -   —(CH₂)₅—,        -   —(CH(R⁴)—CH₂)₃—,        -   —(CH(R⁴)—CH₂)₄—,        -   —(CH(R⁴)—(CH₂)₂—CH(R⁴))—,        -   —(CH(R⁴)—(CH₂)₃—CH(R⁴))—,        -   —CH₂—CH₂-A-CH₂—CH₂—,        -   —CH(R⁴)—CH₂-A-CH₂CH₂—,        -   —CH(R⁴)—CH₂-A-CH₂—CH(R⁴)—    -   wherein R⁴ is alkyl of from one to four carbon atoms, A is O, S,        or N and R is as defined above.

Particularly preferred, is a compound of Formula (6) wherein R is PhCH₂—or (CH₃)₃—C—, and R¹ is

More particularly preferred, is a compound of Formula (6) wherein R isPhCH₂— and R¹ is

A sixth aspect of the present invention is a compound of Formula (8)

-   -   wherein R¹ is as defined above.

Particularly preferred is a compound of Formula (8) wherein R¹ is

A seventh aspect of the present invention is a compound of Formula (10)or a pharmaceutically acceptable salt thereof

-   -   wherein R¹ is as defined above.

Particularly preferred is a compound of Formula (10) wherein R¹ is—O-tertiary butyl, —O-isopropyl, —O-ethyl, —O-methyl,

or —NMe₂.

An eighth aspect of the present invention is the compound of Formula(12)

A ninth aspect of the present invention is a compound of Formula (18) ora pharmaceutically acceptable salt thereof

-   -   wherein R¹ is as defined above.

Particularly preferred is a compound of Formula (18) wherein R¹ is—O-tertiary butyl, —O-isopropyl, —O-ethyl, —O-methyl,

or —NMe₂.

A tenth aspect of the present invention is a compound of Formula (18a)or a pharmaceutically acceptable salt thereof

-   -   wherein R¹ is as defined above.

Particularly preferred is a compound of Formula (18a) wherein R¹ is—O-tertiary butyl, —O-isopropyl, —O-ethyl, —O-methyl,

or —NMe₂.

DETAILED DESCRIPTION OF THE INVENTION

The term “alkyl” means a straight or branched hydrocarbon radical havingfrom 1 to 8 carbon atoms and includes, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like.

“Alkoxy” and “thioalkoxy” are O-alkyl or S-alkyl of from 1 to 6 carbonatoms as defined above for “alkyl”.

The term “cycloalkyl” means a saturated hydrocarbon ring having 3 to 8carbon atoms and includes, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term “aryl” means an aromatic radical which is a phenyl group, aphenylalkyl group, a phenyl group substituted by 1 to 4 substituentsselected from alkyl as defined above, alkoxy as defined above,thioalkoxy as defined above, halogen, trifluoromethyl, dialkylamino asdefined above for alkyl, nitro, cyano,

as defined above for alkyl, —(CH₂)_(n)2-N(alkyl)₂ wherein n² is aninteger of 1 to 5 and alkyl is defined aboveand

as defined above for alkyl and n².

The term “allyl” means a hydrocarbon radical of 3 to 8 carbon atoms,containing a double bond between carbons 2 and 3, unsubstituted orsubstituted by 1 to 3 substituents on the carbons containing the doublebond selected from alkyl or aryl as defined above, and includes, forexample, propenyl, 2-butenyl, cinnamyl, and the like.

The term “arylalkyl” means an aromatic radical attached to an alkylradical wherein aryl and alkyl are as defined above for example, benzyl,phenylethyl, 3-phenylpropyl, (4-chlorophenyl)methyl, and the like.

“Alkali metal” is a metal in Group IA of the periodic table andincludes, for example, lithium, sodium, potassium, and the like.

“Alkaline-earth metal” is a metal in Group IIA of the periodic table andincludes, for example, calcium, barium, strontium, magnesium, and thelike.

The term “heteroaryl” means a 5- and 6-membered heteroaromatic radicalwhich may optionally be fused to a benzene ring containing 1 to 3heteroatoms selected from N, O, and S and includes, for example, aheteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or5-pyrimidinyl, 3- or 4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5-yl,1H-benzimidazol-6-yl, 1H-benzimidazol-5-yl, 2-, 4-, or 5-thiazolyl, 3-,4-, or 5-isothiazolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl,or 2- or 5-thiadiazolyl and the like optionally substituted by asubstituent selected from alkyl as defined above, alkoxy as definedabove, thioalkoxy as defined above, halogen, trifluoromethyl,dialkylamino as defined above for alkyl, nitro, cyano,

as defined above for alkyl, —(CH2)_(n)2-N(alkyl)₂ wherein n² is aninteger of 1 to 5, and alkyl is as defined above, and

asdefined above for alkyl and n².

Pharmaceutically acceptable acid addition salts of the compounds of thepresent invention include salts derived from inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,hydrofluoric, phosphorous, and the like, as well as the salts derivedfrom nontoxic organic acids, such as aliphatic mono- and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate,oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate,mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate,lactate, maleate, tartrate, methanesulfonate, and the like. Alsocontemplated are salts of amino acids such as arginate and the like andgluconate, galacturonate (see, for example, Berge S. M. et al.,“Pharmaceutical Salts,” J. of Pharma. Sci., 1977;66:1).

The acid addition salts of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise the salts areequivalent to their respective free base for purposes of the presentinvention.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines.Examples of metals used as cations are sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines areN,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine(see, for example, Berge S. M. et al., “Pharmaceutical Salts,” J. ofPharma Sci., 1977;66: 1).

The base addition salts of said acidic compounds are prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner. The free acid formmay be regenerated by contacting the salt form with an acid andisolating the free acid in the conventional manner. The free acid formsdiffer from their respective salt forms somewhat in certain physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid for purposes of the presentinvention.

Additionally, the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

The following list contains abbreviations and acronyms used within theschemes and text:

-   H₂SO₄ Sulfuric acid-   NaOMe Sodium methoxide-   MeOH Methanol-   MtBE Methyl tert-butyl ether-   GC Gas chromatography-   Pt/C Platinum on carbon-   Pd/C Palladium on carbon-   H₂ Hydrogen-   HCl Hydrochloric acid-   Hg Mercury-   psi Pounds per square inch-   iPrOH (IPA) Isopropyl alcohol-   HPLC High pressure liquid chromatography-   NaOH Sodium hydroxide-   CH₂Cl₂ Dichloromethane (methylene chloride)-   DMSO-d₆ Deuterated dimethylsulfoxide-   THF Tetrahydrofuran-   Na₂SO₄ Sodium sulfate-   nBuLi n-Butyllithium-   NaCl Sodium chloride-   KOtBu Potassium tert-butoxide-   NaHCO₃ Sodium bicarbonate-   BnOH Benzyl alcohol-   Pd(OH)₂/C Palladium hydroxide on carbon-   H₂O Water-   PivOH Pivalic acid-   PhCHO Benzaldehyde-   PhCH₃ Toluene-   CDCl₃ Deuterated chloroform-   BnONa Sodium benzylate-   NH₄OH Ammonium hydroxide-   PhCH(OMe)₂ Benzaldehyde dimethyl acetal-   MsOH Methanesulfonic acid-   pTsOH para Toluenesulfonic acid-   CSA Camphorsulfonic acid-   Ph Phenyl-   NaH Sodium hydride-   KH Potassium hydride-   EtOAc Ethyl acetate-   tBuOH(HOtBu) tert-Butanol-   PhCH₂CO₂H Phenylacetic acid-   NaNH₂ Sodium amide-   KHMDS Potassium hexamethyldisilazide-   LAH Lithium aluminum hydride-   Pd/Al₂O₃ Palladium on alumina-   APCI Atmospheric pressure chemical ionization-   ESI Electrospray ionization-   DCI Direct chemical ionization-   ¹H NMR Proton nuclear magnetic resonance spectroscopy-   ¹³C NMR¹³Carbon nuclear magnetic resonance spectroscopy-   BINAP (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl-   pTol-BINAP (R)-(+)-Bis(di-p-tolyl-phosphino)-1,1′-binaphthyl-   C1-MeO-BIPHEP [(R)-(+)-5,5′-Dichloro-6,6′-dimethoxy    [1,1′-biphenyl]-2,2′-diyl]-bis-diphenylphosphine-   C2-TunaPhos [(12aR)-6,7-dihydrodibenzo[e,g]    [1,4]dioxocin-1,12-diyl]-bis-diphenylphosphine-   C4-TunaPhos    [(14aR)-6,7,8,9-tetrahydrodibenzo[b,d][1,6]dioxecin-1,14-diyl]-bis-diphenylphosphine-   MeO-BIPHEP [(1S)-(−)-6,6′-Dimethoxy    [1,1′-biphenyl]-2,2′-diyl]-bis-diphenylphosphine-   p-cymene 4-isopropyltoluene-   ee Enantiomeric excess-   HRMS High resolution mass spectrometry-   m/z Mass to charge ratio-   t_(R) Retention time

The process of the present invention in its first aspect is a new,improved, economical, and commercially feasible method for thepreparation of the compound of Formula (13)

The process of the present invention in its first aspect is outlined inScheme 1. Thus, a compound of Formula (1) wherein R is alkyl, aryl,arylalkyl, or heteroaryl is reacted with a compound of Formula (2)wherein R¹ is —XR wherein

-   -   X is O,    -   S,    -   Se or R¹ is    -   wherein R² or R³ is independently        -   alkyl,        -   cycloalkyl,        -   arylalkyl, or        -   aryl, or        -   R² and R³ together are        -   —(CH₂)₄—,        -   —(CH₂)₅—,        -   —(CH(R⁴)—CH₂)₃—,        -   —(CH(R⁴)—CH₂)₄—,        -   —(CH(R⁴)—(CH₂)₂—CH(R⁴))—,        -   —(CH(R⁴)—(CH₂)₃—CH(R⁴))—,        -   —CH₂—CH₂-A-CH₂—CH₂—,        -   —CH(R⁴)—CH₂-A-CH₂CH₂—,        -   —CH(R⁴)—CH₂-A-CH₂—CH(R⁴)—    -   wherein R⁴ is alkyl of from one to four carbon atoms, A is O, S,        or N and R is as defined above in a solvent such as, for        example, methyl tertiary butyl ether, and the like, to afford a        compound of Formula (3) whereas R¹ is as defined above.        Preferably, the reaction is carried out with a compound of        Formula (2) wherein R¹—H is morpholine in methyl tertiary butyl        ether.

A compound of Formula (3) is reacted with hydrogen in the presence of acatalyst such as, for example, Pt/C, Pd/C in the presence of an acidsuch as, for example, a strong acid, for example, hydrochloric acid,hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, sulfuricacid, and the like (optionally the reduction is carried out with SpongeNi/NH₄OH, metal hydrides, and the like, to afford the free base of acompound of Formula (4)) in a solvent such as, for example, methanol,ethanol, and the like to afford a compound of Formula (4) wherein Y isCl, Br, TsO, MsO, or HSO₄ and R¹ is as defined above.

Preferably, the reaction is carried out in the presence of Pt/C,hydrochloric acid and hydrogen in methanol.

A compound of Formula (4) is reacted with a base such as, for example,sodium methoxide and the like in a solvent such as, for example,tetrahydrofuran, toluene, methyl tertiary butyl ether, and the like, andin an alcohol such as, for example, isopropanol, ethanol, methanol, andthe like, to afford the free base followed by reaction with a compoundof Formula (5) wherein R is as defined above in a solvent such as, forexample, isopropanol, tetrahydrofuran, and the like to afford a compoundof Formula (6) wherein R is as defined above. Optionally, the free baseof a compound of Formula (4) may be reacted with a compound of Formula(5) to afford a compound of Formula (6). Preferably, the reaction iscarried out with sodium methoxide in methyl tertiary butyl ether andmethanol to afford the free base followed by reaction with phenylaceticin tetrahydrofuran.

A compound of Formula (6) is reacted with the compound of Formula (7) ina solvent such as, for example, a protic, an aprotic, a polar or anon-polar solvent, for example, tetrahydrofuran and the like withremoval of water with the aid of a chemical drying agent such as, forexample, molecular sieves and the like or with the aid of a Dean-Starkwater trap or using azeotropic distillation with a suitable solvent suchas, for example toluene and the like to afford a compound of Formula (8)wherein R¹ is as defined above. Preferably, the reaction is carried outwith activated 3A molecular sieves in tetrahydrofuran.

A compound of Formula (8) is reacted with a compound of Formula (9)wherein M is sodium, lithium, potassium, zinc, magnesium, copper,calcium, or aluminum and R¹ is as defined above in a solvent such as,for example, a nonreactive aprotic solvent, for example,tetrahydrofuran, toluene, and the like in the presence of a strong basesuch as, for example, n-butyllithium, lithium or potassiumhexamethyldisilazide, lithium diisopropylamide, and the like to afford acompound of Formula (10) wherein R¹ is as defined above. Preferably, thereaction is carried out with a compound of Formula (9) wherein M issodium, the base is n-butyllithium and the solvent is tetrahydrofuran.

The carbonyls of a compound of Formula (10) in Scheme 1 are shown in theketo form. However, a compound of Formula (10) can undergo “keto-enol”tautomerism and thus can exist in several tautomeric forms which areencompassed within the present invention.

A compound of Formula (10) is treated with hydrogen in the presence of acatalyst such as, for example, a chiral non-racemic ruthenium(II)-diphosphine complex. For example, a ruthenium catalyst precursorsuch as [dichloro-(1,5-cyclooctadiene)] ruthenium (II) oligomer andchiral diphosphine ligand such as[(R)-(+)-2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl]. However, anychiral non-racemic ruthenium (II)/diphosphine combination may beemployed in this reduction reaction. For example, ruthenium (II)catalyst precursors include [dibromo-(1,5-cyclooctadiene)] ruthenium(II) dimer, [bis-(2-methallyl)cycloocta-1,5-diene] ruthenium (II)complex and [dichloro(p-cymene)] ruthenium (II) dimer, and the like.Examples of effective chiral diphosphine ligands include2,2′-bis(di-p-tolyl-phosphino)-1,1′-binaphthyl,2-diphenyl-phosphinomethyl-4-diphenylphosphino-1-tert-butoxy-carbonylpyrrolidine,tricyclo[8.2.2.24,7]hexadeca-4,6,10,12,13,15-hexaene-5,11-diyl-bis(diphenylphosphine) derivatives,4,4′-bidibenzofuran-3,3′-diylbis(diphenylphosphine),6,6′-dimethoxy[1,1′-biphenyl]-2,2′-diyl]bis-diphenylphosphine,[5,5′-dichloro-6,6′-dimethoxy[1,1′-biphenyl]-2,2′-diyl]-bis-diphenylphosphine,and 1,2-bis(2,5-dimethylphospholano) derivatives and the like in asolvent such as, for example, methanol, ethanol, isopropanol, and thelike, optionally in the presence of a co-solvent, for example,dichloromethane, tetrahydrofuran, toluene and the like in the presenceof an acid such as, for example, hydrochloric acid, hydrobromic acid,Dowex® ion exchange resin, and the like to afford a compound of Formula(11) or a compound of Formula (11a) wherein R¹ is as defined above.Preferably, the reaction is carried out with dichloro(p-cymene)ruthenium (II) dimer and[(R)-(+)-5,5′-dichloro-6,6′-dimethoxy[1,1′-biphenyl]-2,2′-diyl]-bis-diphenylphosphinein methanol in the presence of hydrobromic acid.

A compound of Formula (11b) wherein R¹a is wherein R^(1a) is OH, —XRwherein

-   -   X is O,    -   S, or    -   Se, or R^(1a) is    -   wherein R² or R³ is independently        -   alkyl,        -   cycloalkyl,        -   arylalkyl, or        -   aryl, or        -   R² and R³ together are        -   —(CH₂)₄—,        -   —(CH₂)₅—,        -   —(CH(R⁴)—CH₂)₃—,        -   —(CH(R⁴)—CH₂)₄—,        -   —(CH(R⁴)—(CH₂)₂—CH(R⁴))—,        -   —(CH(R⁴)—(CH₂)₃—CH(R⁴))—,        -   —CH₂—CH₂-A-CH₂—CH₂—,        -   —CH(R⁴)—CH₂-A-CH₂CH₂—,        -   —CH(R⁴)—CH₂-A-CH₂—CH(R⁴)—    -   wherein R⁴ is alkyl of from one to four carbon atoms, A is O, S,        or N, and R is alkyl, aryl, arylalkyl, or heteroaryl is reacted        with an acid such as, for example, p-toluenesulfonic acid,        camphor-sulfonic acid, sulfuric acid, hydrogen chloride, and the        like in a non-nucleophilic solvent such as, for example,        toluene, acetonitrile, dichloromethane, methyl tertiary butyl        ether, and the like, followed by reaction with a base, such as,        for example, triethylamine, pyridine, diisopropylethylamine, and        the like, and with an acylating agent, such as, for example,        acetic anhydride, benzoyl chloride, benzyl chloroformate, and        the like, in the presence of 4-dimethylaminopyridine to afford        the compound of Formula (12). Preferably, the reaction is        carried out in toluene in the presence of p-toluenesulfonic        acid, followed by treatment with triethylamine, acetic        anhydride, and 4-dimethylaminopyridine in toluene.

A compound of Formula (12) is reacted with HO-M in an alcohol of Formula(17) or (17b) wherein M is sodium, lithium, potassium, zinc, magnesium,copper, calcium, or aluminum, or with a compound of Formula (16) or(16b) wherein M is as defined above in an alcohol of Formula (17) or(17b) wherein aryl or allyl in a compound of Formula (16) or (16b) and(17) or (17b) is the same, in an optional cosolvent, such as, forexample, a normucleophilic solvent, for example, acetone,tetrahydrofuran, 1,2-dimethoxyethane, and the like, followed by theaddition of hydrogen in the presence of a catalyst, such as, forexample, Pd(OH)₂/C, Pd/C, Pd/Al₂O₃, and the like, in the presence of anacid, such as, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, and the like, to afford the compound of Formula (13).Preferably, the reaction is carried out with sodium hydroxide in benzylalcohol followed by hydrogenation in the presence of Pd(OH)₂/C andsulfuric acid.

The process of the present invention in its second aspect is outlined inScheme 2. Thus, a compound of Formula (4), prepared as described inScheme 1, is reacted with a compound of Formula (20) wherein R and M areas defined above and a compound of Formula (7) with removal of waterwith the aid of a chemical drying agent such as, for example, molecularsieves and the like or with the aid of a Dean-Stark water trap or usingazeotropic distillation with a suitable solvent such as, for exampletetrahydrofuran, toluene, and the like, to afford a compound of Formula(8) wherein R¹ is as defined above. Preferably, the reaction is carriedout with a compound of Formula (20) wherein R is PhCH₂ and M is sodiumin the presence of activated 3A molecular seives in tetrahydrofuran.

The process of the present invention in its third aspect is outlined inScheme 3. Thus, a compound of Formula (11) is reacted with an acetal ofFormula (15) wherein R⁵ and R⁵a are independently the same or differentand are, methyl, ethyl, or —(CH₂)_(n)— wherein n is an integer of 2 to4, and R is as defined above in the presence of an acid such as, forexample, hydrochloric acid, pyridinium p-toluenesulfonate,p-toluenesulfonic acid and the like in a solvent such as, for example,toluene, dichloromethane, methyl tertiary butyl ether, and the like,followed by the addition of an aldehyde corresponding to the previousacetal of Formula (15) in the presence of a strong base such as, forexample, a non-nucleophilic base, for example, potassium tertiarybutoxide, potassium bis(trimethylsilyl) amide, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like, to afford a compound of Formula (14) whereinR¹ and R are as defined above. Preferably, the reaction is carried outwith benzaldehyde dimethyl acetal in toluene in the presence ofp-toluenesulfonic acid followed by the addition of benzaldehyde andpotassium tertiary butoxide in tetrahydrofuran.

A compound of Formula (14) is reacted with hydrogen in the presence of acatalyst such as, for example, palladium on carbon or platinum on carbonand the like in the presence of an acid such as, for example,hydrochloric acid and the like in a solvent such as, for example,toluene, tetrahydrofuran, methyl tertiary butyl ether, ethyl acetate,and the like, and an alcohol, such as, for example, methanol, ethanol,and the like, to afford a compound of Formula (13). Preferably, thereaction is carried out in toluene in the presence of platinum on carbonin the presence of methanol in the presence of hydrochloric acid.

Optionally, a compound of Formula (14) is reacted with an acid such as,for example, hydrochloric acid, pyridinium p-toluenesulfonate,p-toluenesulfonic acid, and the like, in a solvent such as, for example,toluene, dichloromethane, methyl tertiary butyl ether, and the like toafford the compound of Formula (13). Preferably, the reaction is carriedout in methylene chloride in the presence of p-toluenesulfonic acid.

Alternatively, a compound of Formula (11) is reacted with an acid, suchas, for example, hydrochloric acid, hydrobromic acid, p-toluenesulfonicacid, and the like, in a non-nucleophilic solvent, such as, for example,toluene, acetonitrile, methyl tertiary butyl ether, tetrahydrofuran, andthe like, to afford a compound of Formula (13). Preferably, the reactionis carried out in toluene in the presence of p-toluenesulfonic acid.

The process of the present invention in its fourth aspect is outlined inScheme 4. Thus, a compound of Formula (10) wherein R¹ is as definedabove is reacted with one molar equivalent of hydrogen in the presenceof a catalyst using the methodology described above for the conversionof a compound of Formula (10) to a compound of Formula (11) to affordeither a compound of Formula (18) or Formula (18a) wherein R¹ is asdefined above or a mixture thereof. A mixture of compounds of Formula(18) and (18a) may be separated using conventional methodology, such as,for example, chromatography and the like. Preferably, a mixture ofcompounds of Formula (18) and (18a) is separated using HPLC.

A compound of Formula (18) or (18a) or a mixture thereof is reacted withhydrogen in the presence of a catalyst as described above for preparinga compound of Formula (11) to afford a compound of Formula (11b) whereinR¹a is as defined above. Preferably, the reaction is carried out usingat least one molar equivalent of hydrogen.

The compound of Formula (13) can be converted to atorvastatin calcium(19) using the procedures disclosed in U.S. Pat. No. 5,273,995 and5,969,156.

The following nonlimiting examples illustrate the inventors' preferredmethods for preparing the compounds of the invention.

EXAMPLE 15-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide Step 1: 3-Morpholin-4-yl-3-oxo-propionitrile

A nitrogen inerted reactor equipped with reflux condenser, nitrogeninlet and mechanical stirring is charged with morpholine (1.2 mol),methyl cyanoacetate (1.0 mol) and MtBE (52 mL). The homogeneous solutionis heated to ca. 55° C. and stirred at that temperature for 12 to 18hours. MtBE (33 mL) is added over ca. 15 minutes, and the solution isslowly cooled below 50° C. where nucleation becomes evident. AdditionalMTBE (66 μL) is added over a 1-hour period. During this time, thereaction is allowed to cool to near ambient temperature. After completeMtBE addition, the reaction is cooled with stirring to ca. 0° C. Theresulting precipitate is collected via filtration and the cake is washedwith additional MtBE (ca. 40 mL). The solid is dried under vacuum at ca.45° C. to provide 3-morpholin-4-yl-3-oxo-propionitrile (139 g). Thismaterial is used in subsequent steps without further purification.

m/z (APCI(m+1)) 154.9;calcd for C₇H₁₀N₂O₂ 154.07.

Step 2: 3-Amino-1-morpholin-4-yl-propan-1-one; hydrochloride

A nitrogen inerted reactor is charged with 5% Pt-C (43 g; 58% water-wet)followed by 3-morpholin-4-yl-3-oxo-propionitrile (2.8 mol). A solutionof MeOH (3.4 L) and 12N HCl (3.08 mol) is added at such a rate as tomaintain an internal temperature of ca. 25° C. The vessel and itscontents are degassed via three N₂ pressure purges (50 psi). Theatmosphere is switched to hydrogen via three H₂ pressure purges (50psi), and the reaction is stirred vigorously at ca. 25° C. under asustained pressure of hydrogen (50 psi) for ca. 24 hours. The H₂pressure is released and replaced with N₂. The reaction is passedthrough filter agent, which is subsequently washed with MeOH (500 mL).The reaction is concentrated in vacuo to a volume of ca. 1.4 L, and IPA(2.2 L) is added. The reaction mixture is cooled to 0° C. and filtered.The filter cake is washed with MtBE (500 mL) and dried under vacuum atca. 30° C. to provide 3-amino-1-morpholin-4-yl-propan-1-one,hydrochloride as a white solid (439 g). This material is used insubsequent steps without further purification.

¹H NMR (400 MHz, DMSO) δ 2.72 (t, 2H, J=6.78), 2.96 (t, 2H, J=6.77),3.83-3.44 (m, 2H), 3.52-3.58 (m, 2H), 8.08 (bs, 3H).

¹³C NMR (100 MHz, DMSO) δ 168.4, 65.9, 45.1, 41.45, 35.1, 29.6.

Free base: m/z (APCI(m+1)) 159.2; calcd for C₇H₁₄N₂O₂ 158.11.

Step 3: 3-Amino-1-morpholin-4-yl-propan-1-one; compound withphenylacetic acid

A reactor is charged with 3-amino-1-morpholin-4-yl-propan-1-one;hydrochloride (765 mmol). MeOH (380 mL) is added, and the mixture isstirred vigorously at room temperature for ca. 10 minutes. MtBE (380 mL)is added and the resulting slurry is cooled to −10° C., where a 25%(w/w) MeOH solution of NaOMe (765 mmol) is added slowly via additionfunnel at such a rate as to maintain an internal temperature of ca. −10°C. The resulting suspension is stirred vigorously under a N₂ atmosphereas it is allowed to warm to 0° C. Solids are removed via filtration,rinsing with additional MtBE (50 mL). Solvent is removed in vacuo toprovide the free base as a crude oil that is taken up in MtBE (600 mL).The mixture is cooled with vigorous agitation to ca. 0° C., wherephenylacetic acid (765 mmol) is added slowly as a solution in MtBE (300mL). The reaction mixture is stirred an additional 10 minutes aftercomplete addition, during which time the product precipitates out ofsolution. The solids are collected via filtration, washed withadditional MtBE (100 mL) and dried under vacuum at <40° C. to provide3-amino-1-morpholin-4-yl-propan-1-one; compound with phenylacetic acid(191 g). This material is carried on to subsequent steps without furtherpurification, or optionally, it can be re-precipitated from MtBE.

¹H NMR (400 MHz, DMSO) δ 2.55 (t, 2H, J=6.78), 2.86 (t, 2H, J=6.78) 3.62(t, 2H), 3.42 (t, 2H), 6.22 (bs, 3H), 7.25-7.12 (m, 5H).

¹³C NMR (100 MHz, DMSO) δ 174.2, 169.0, 138.2, 129.2, 127.8, 125.5,66.0, 45.2, 44.4, 41.4, 35.7, 31.6.

Step 4:5-(4-Fluorophenyl)-2-isopropyl-1-(3-morpholin-4-yl-3-oxo-propyl)-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide

Method A

A nitrogen inerted reactor, equipped with a suitable reflux condenserand soxhlet extractor containing freshly activated 3A molecular sieves(4-8 mesh; 97.2 g), is charged with3-amino-1-morpholin-4-yl-propan-1-one, compound with phenylacetic acid(765 mmol) and2-[2-(4-fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoicacid phenylamide (450 mmol). THF (360 mL) is added, and the resultingsolution is stirred vigorously as the reaction is heated at refluxtemperature for ca. 24 hours, during which time the product begins toprecipitate. Half-saturated aqueous NaHCO₃ (100 mL) is added, and thereaction mixture is cooled with continued stirring to ca. 0° C. MtBE(100 mL) is added, and the solids are collected via filtration. Thesolid is washed with distilled water (100 mL) and MtBE (2×100 mL),collected, and dried under vacuum at <50° C. to afford5-(4-fluorophenyl)-2-isopropyl-1-(3-morpholin-4-yl-3-oxo-propyl)-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide as a white solid (194 g). This material is carried onto subsequent steps without further purification.

m/z (APCI(m⁻¹)) 538.2; (APCI(m+1) 540.2; calcd for C₃₃H₃₄FN₃O₃ 539.26.Method B

A nitrogen inerted reactor, equipped with a suitable reflux condenserand soxhlet extractor containing freshly activated 3A molecular sieves(4-8 mesh; 36 g), is charged with 3-amino-1-morpholin-4-yl-propan-1-onehydrochloride (170 mmol), phenylacetic acid sodium salt (170 mmol) and2-[2-(4-fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoicacid phenylamide (100 mmol). THF (150 mL) is added, and the resultingsolution is stirred vigorously as the reaction is heated at refluxtemperature for ca. 24 hours, during which time the product begins toprecipitate. Aqueous NaHCO₃ (100 mL) is added slowly, and the reactionmixture is cooled with continued stirring to ca. 0° C. MtBE (100 ML) isadded, and the solids are collected via filtration. The yellow-coloredsolid is washed with distilled water (15 mL) and MtBE (2×15 mL),collected, and dried under vacuum at <50° C. to afford5-(4-fluorophenyl)-2-isopropyl-1-(3-morpholin-4-yl-3-oxo-propyl)-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide as a white solid (42.1 g). This material is carried onto subsequent steps without further purification.

m/z (APCI(m−1)) 538.2; (APCI(m+1) 540.2; calcd for C₃₃H₃₄FN₃O₃ 539.26.Method C

A nitrogen inerted reactor equipped with reflux condenser, nitrogeninlet and mechanical stirring is charged with morpholine (1.2 mol),methyl cyanoacetate (1.0 mol), and MtBE (52 mL). The homogeneoussolution is heated to ca. 55° C. and stirred at that temperature for 12to 18 hours. MtBE (33 mL) is added over ca. 15 minutes, and the solutionis slowly cooled below 50° C. until nucleation becomes evident.Additional MtBE (66 mL) is added over a 1-hour period. During this time,the reaction is allowed to cool to near ambient temperature. Aftercomplete MtBE addition, the reaction is cooled with stirring to ca. 0°C. The resulting precipitate is collected via filtration and the cake iswashed with additional MtBE (40 mL). The crude3-morpholin-4-yl-3-oxo-propionitrile is taken up in MeOH (2 L) andtransferred to a nitrogen inerted pressure reactor that has been chargedwith 5% Pt-C (55 g; 58% water-wet). HCl (12 N, 1.1 mol) is added at sucha rate as to maintain an internal temperature of ca. 25° C. The vesseland its contents are degassed via three N₂ pressure purges (50 psi). Theatmosphere is switched to hydrogen via three H₂ pressure purges (50psi), and the reaction is stirred vigorously at ca. 25° C. under asustained pressure of hydrogen (50 psi) for ca. 24 hours. The H₂pressure is released and replaced with N₂. The reaction is passedthrough filter agent, which is subsequently washed with MeOH (500 mL).The reaction is concentrated to a MeOH-wet solid, which is reslurried inIPA (100 mL). The slurry is cooled to 0° C. and filtered. The filtercake is washed with cold (0° C.) IPA (75 mL) and reslurried in MeOH (500ML) and MtBE (500 mL). The slurry is cooled with agitation to −10C wherea 25% (w/w) solution of NaOMe in MeOH (1 mol) is added dropwise at sucha rate as to maintain an internal reaction temperature of ≦−5° C. Theresulting suspension is filtered to afford a clear solution of freebase. The solvent is removed in vacuo to provide a crude oil that istaken up in THF (450 mL) and cooled to ca. 0° C. This solution istransferred into a nitrogen inerted reactor that contains phenylaceticacid (1.0 mol) and2-[2-(4-fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoicacid phenylamide (590 mmol). The reactor is equipped with a suitablereflux condenser and soxhlet extractor containing freshly activated 3Amolecular sieves (4-8 mesh; 125 g). The resulting solution is stirredvigorously as the reaction is refluxed under a N₂ atmosphere for ca. 24hours, during which time the product begins to precipitate.Half-saturated aqueous NaHCO₃ (130 mL) is added slowly, and the reactionmixture is cooled with continued stirring to ca. 0° C. MtBE (130 mL) isadded, and the solids are collected via filtration. The solid is washedwith distilled water (130 mL) and MtBE (2×130 mL), collected, and driedunder vacuum at <50° C. to afford5-(4-fluorophenyl)-2-isopropyl-1-(3-morpholin-4-yl-3-oxo-propyl)-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide as a white solid (223 g). This material is carried onto subsequent steps without further purification.

m/z (APCI(m−1)) 538.2; (APCI(m+1) 540.2; calcd for C₃₃H₃₄FN₃O₃ 539.26.

Step 5:7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoicacid, ethyl ester

Method A

A dry, nitrogen inerted reactor is charged with sodium hydride (300mmol). Anhydrous THF (150 mL) is added and the resulting mixture iscooled under nitrogen to ca. −20° C. Ethyl acetoacetate (307 mmol) isadded at such a rate as to maintain an internal reaction temperature of≦−10° C. The addition is followed by a T1F rinse (30 mL) and theresulting solution is stirred for approximately 45 minutes at ≦−10° C.The temperature is allowed to cool to ca. −18° C. A 10.0 M solution ofn-BuLi in hexanes (300 mmol) is added at such a rate as to maintain aninternal reaction temperature of ≦−4° C. The addition is followed by aTHF rinse (30 mL) and the resulting orange solution is stirred for about90 minutes at ≦−4° C. The temperature is allowed to cool to ca. −25° C.To the solution of dienolate is added5-(4-fluorophenyl)-2-isopropyl-1-(3-morpholin-4-yl-3-oxo-propyl)-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide (74 mmol), and the resulting slurry is stirred at ca.−23° C. for 20 hours. The reaction is quenched into a mixture of 18%aqueous HCl (898 mmol) and MTBE (20 mL) at such a rate as to maintain aninternal reaction temperature of ≦−2° C. The reactor and transfer systemis rinsed with THF (30 mL) and transferred to the reaction mixture. Thetwo-phase solution is allowed to warm to ca. 20° C. with stirring. Themixture is transferred to a separatory funnel, and the phases areallowed to separate. The organic layer is washed with water (33 mL) andsaturated aqueous NaCl (33 mL). All aqueous layers are back-extractedwith MtBE (40 mL). The two organic layers are combined and concentratedin vacuo to a crude oil maintaining an internal batch temperature of≦60° C. EtOH (24 ML) is added to the oil and, again, the mixture isconcentrated in vacuo. EtOH (330 mL) and water (33 mL) are immediatelyadded to the resulting oil, and the solution of product is allowed tostand at ≦10° C. for ca. 14 hours. The resulting solid is collected,washed with cold 20% aqueous EtOH (100 mL) and dried in vacuo to afford7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoicacid, ethyl ester (35.6 g) as a white solid. This material is carried onto subsequent steps without further purification, or optionally, it canbe re-precipitated from IPA/H₂O.

HRMS m/z (ESI(m−1)) 581.2463; calcd for C₃₅H₃₅FN₂O₅ 582.2530.

In a process analogous to Step 5 METHOD A, by substituting theappropriate ester or amide of acetoacetic acid for ethyl acetoacetate,one obtains the following compounds:

-   7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic    acid, tert-butyl ester.

HRMS m/z (ESI(m−1)) 609.2772; APCI(m+1) 611.3; calcd for C₃₇H₃₉FN₂O₅610.2843.

-   7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic    acid, isopropyl ester.

m/z (DCI(m+1)) 597; calcd for C₃₆H₃₇FN₂O₅ 596.27.

-   7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic    acid, methyl ester.

m/z (DCI(m+1)) 569; calcd for C₃₄H₃₃FN₂O₅ 568.24.

-   7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic    acid, morpholino amide.

HRMS m/z (ESI(m−1)) 622.2715; calcd for C₃₇H₃₈FN₃O₅ 623.2795.

-   7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic    acid, N,N-dimethyl amide.

m/z (DCI(m+1)) 582; calcd for C₃₅H₃₆FN₃O₄ 581.27.

Method B

7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoicacid, tert-butyl ester

A nitrogen inerted reactor is charged with the sodium salt of tert-butylacetoacetate (100 mmol). Anhydrous toluene (71.5 mL) and THF (8.2 mL,101 mmol) are added, and the resulting solution is cooled under apositive pressure of nitrogen to ca.−10° C. A 10 M hexanes solution ofn-BuLi (104 mmol) is added at such a rate as to maintain an internalreaction temperature of <1° C. The resulting solution is stirred anadditional 20 to 30 minutes after complete addition as the temperatureis allowed to cool to ca. −6° C. Meanwhile,5-(4-fluorophenyl)-2-isopropyl-1-(3-morpholin-4-yl-3-oxo-propyl)-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide (25 mmol) is charged to a second nitrogen inertedreactor. Anhydrous THF (50 mL) is added at room temperature, and theresulting slurry is cooled to ca. −10° C. and stirred for 15 to 90minutes. The solution of dienolate is added to the slurry of morpholineamide at such a rate as to maintain an internal reaction temperature ca.−5° C. Following this addition, the slurry is stirred at ca. −5° C.for >2 hours. Water (35 mL) is added with vigorous agitation at such arate as to maintain an internal reaction temperature of <0° C.Concentrated 37% hydrochloric acid (19.0 mL, 229 mmol) is added at sucha rate as to maintain an internal reaction temperature of ≦0° C. Thetwo-layered reaction mixture is vacuum distilled, removing >50% of theorganic solvents. The distillation is stopped and the lower aqueouslayer is discarded. Water (55 mL) is added and the vacuum distillationis continued until a majority of the organic solvents are removed.[Note: It is preferable to drain and replace the aqueous layer beforeinitiating the vacuum distillation.] IPA (100 mL) is added followed bywater (100 mL). The mixture is stirred for >6 hours, allowing forsolidification of the product. The solid is collected via filtration,and the cake is washed with pre-mixed 1:1 IPA:H₂O. The resulting solidis dried in vacuo at 35° C. to provide7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoicacid, tert-butyl ester (14.1 g) as a white solid. This material iscarried on to subsequent steps without further purification, oroptionally, it can be re-precipitated from toluene.

HRMS m/z (ESI(m−1)) 609.2772; APCI(m+1) 611.3; calcd for C₃₇H₃₉FN₂O₅610.2843.

In a process analogous to Step 5 METHOD B, by substituting the sodiumsalt of the appropriate ester or amide of acetoacetic acid for thesodium salt of tert-butyl acetoacetate, one obtains the followingcompounds:

-   7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic    acid, ethyl ester.

HRMS m/z (ESI(m−1)) 581.2463; calcd for C₃₅H₃₅FN₂O₅ 582.2530.

-   7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic    acid, isopropyl ester.

m/z (DCI(m+1)) 597; calcd for C₃₆H₃₇FN₂O₅ 596.27.

-   7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic    acid, methyl ester.

m/z (DCI(m+1)) 569; calcd for C₃₄H₃₃FN₂O₅ 568.24.

-   7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic    acid, morpholino amide.

HRMS m/z (ESI(m−1)) 622.2715; calcd for C₃₇H₃₈FN₃O₅ 623.2795.

-   7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic    acid, N,N-dimethyl amide.    m/z (DCI(m+1)) 582; calcd for C₃₅H₃₆FN₃O₄ 581.27.

Step 6:(5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoicacid, methyl ester

Method A

A nitrogen inerted pressure reactor is charged with7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoicacid, ethyl ester (100.0 mmol) and MeOH (250 mL). The resulting slurryis heated with stirring to ca. 55° C. to afford a homogeneous solution.The vessel and its contents are degassed via three 50 psi pressurepurges with argon. Under a steady flow of argon, 1 M methanolic HBr (7.0mmol) and the RuCl₂(DMF)_(n)[(R)-Cl—MeO-BIPHEP)] catalyst (0.5 mmol) areadded, and the reactor is given an additional 50 psi pressure purge withargon. The atmosphere is switched to hydrogen via three 50 psi pressurepurges. The reaction is stirred vigorously at 65° C. under a sustainedpressure of hydrogen (50 psi) until hydrogen uptake ceases. The reactionis allowed to cool to ambient temperature, and the hydrogen pressure isreleased and replaced with nitrogen. The crude MeOH solution of(5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoicacid, methyl ester is carried on to subsequent steps withoutpurification, or optionally, it can be isolated via flash columnchromatography on silica gel, eluting with ethyl acetate-heptanemixtures.

HPLC analysis (YMC ODS AQ S5; 1 mL/min; 30° C.; 254 μm: CH₃CN/H₂O, 60:40(0-22 min) to 100:0 (27-37 min) to 60:40) indicated a syn:anti ratio of1:1.5. Chiral HPLC analysis (Chiralcel OD-H column; 5% EtOH:Hexanes;t_(R)(3R,5R)=23.1 min./t_(R)(3R,5S)=18.0 min./t_(R)(3S,5S)=24.8min./t_(R)(3S,5R)=19.9 min.) indicated an enantiomeric excess at C—Sof >98%, favoring the (R) configuration.

m/z (DCI(m+1)) 573; calcd for C₃₄H₃₇FN₂O₅ 572.27.

In a process analogous to Step 6 METHOD A, using the appropriatealcoholic solvent in place of MeOH, one obtains the following compounds,for example:

-   (5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic    acid, ethyl ester.

m/z (DCI(m+1)) 587; calcd for C₃₅H₃₉FN₂O₅ 586.28.

Chiral HPLC analysis (Chiralcel OD-H column; 5% EtOH:Hexanes;t_(R)(3R,5R)=17.6 min./t_(R)(3R,5S)=14.7 min./t_(R)(3S,5S)=20.9min./t_(R)(3S,5R)=15.9 min.) indicated an enantiomeric excess at C-5 of≧98%, favoring the (R) configuration.

-   (5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic    acid, isopropyl ester.

m/z (DCI(m+1)) 601; calcd for C₃₆H₄₁FN₂O₅ 600.30.

In a process analogous to Step 6 METHOD A, using the appropriate esteror amide from Step 5 in a non-nucleophilic/non-coordinating solvent(e.g., toluene) in place of MeOH, and acetic acid in place of HBr, onecan avoid transesterification and obtain the following compounds, forexample:

-   (5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic    acid, tert-butyl ester.

m/z (APCI(m+1)) 615.3; calcd for C₃₇H₄₃FN₂O₅ 614.32.

-   (5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic    acid, morpholino amide.

m/z (APCI(m−1+HCO₂H)) 672.3; calcd for C₃₇H₄₂FN₃O₅ 627.31.

-   (5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic    acid, N,N-dimethyl amide.

m/z (APCI(m+1)) 586; calcd for C₃₅H₄₀FN₃O₄ 585.30.

In a process analogous to Step 6 METHOD A, using alternativeRu(II)-chiral diphosphine complexes in place ofRuCl₂(DMF)_(n)[(R)-Cl—MeO-BIPHEP)] as the hydrogenation catalyst, onecan obtain the identical products with varying enantiomeric excess atC-5. For example, in the reduction of7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoicacid, ethyl ester to(5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoicacid, methyl ester proceeded as follows:

-   -   RuCl₂(DMF)_(n)[(R)-(+)-BINAP] complex provided product with 90%        ee (favoring the (R) configuration) at C—S as determined by        chiral HPLC analysis.    -   RuCl₂(DMF)_(n)[(R)-(+)-pTol-BINAP] complex provided product with        91% ee (favoring the (R) configuration) at C—S as determined by        chiral HPLC analysis.    -   RuCl2(DMF)_(n)[(R)-(+)—C4-TunaPhos] complex provided product        with 93% ee (favoring the (R) configuration) at C—S as        determined by chiral HPLC analysis.    -   RuCl₂(DMF)_(n)[(R)-(+)—C2-TunaPhos] complex provided product        with 98% ee (favoring the (R) configuration) at C—S as        determined by chiral HPLC analysis.    -   RuCl₂(DMF)_(n)[(S)-(−)-MeO-BIPHEP] complex provided product with        95% ee (favoring the (S) configuration) at C—S as determined by        chiral HPLC analysis.    -   RuCl₂[(R)-(+)-Cl—MeO-BIPHEP] (NEt₃)_(n) complex provided product        with ≧98% ee (favoring the (R) configuration) at C-s as        determined by chiral HPLC analysis.    -   RuCl₂[(R)-(+)-BINAP] (NEt3)_(n) complex provided product with        91% ee (favoring the (R) configuration) at C-s as determined by        chiral HPLC analysis.    -   RuCl₂[(R)-(+)-pTol-BINAP] (NEt3)_(n) complex provided product        with 91% ee (favoring the (R) configuration) at C-s as        determined by chiral HPLC analysis.    -   [Ru(TFA)₂((R)-(+)-Cl—MeO-BIPHEP)]_(n) complex provided product        with ≧98% ee (favoring the (R) configuration) at C-s as        determined by chiral HPLC analysis.    -   [Ru(TFA)₂((R)-(+)-BINAP)]_(n) complex provided product with 90%        ee (favoring the (R) configuration) at C—S as determined by        chiral HPLC analysis.        Method B

A nitrogen inerted pressure reactor is charged with benzene ruthenium(II) chloride dimer (11 mg) and (R)-(+)-C2-TunaPhos (26 mg). The reactoris given a pressure purge with N₂ and N₂-sparged MeOH (1.0 mL) is addedvia syringe. The resulting mixture is thoroughly purged with N₂ andstirred at 25° C. for 30 minutes. A solution of7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoicacid, tert-butyl ester (0.5 g) in N₂-sparged MeOH (4.5 mL) is added tothe reactor via syringe, and the resulting mixture is allowed to stirunder N₂ at 60° C. for 30 minutes. The solution is stirred at 60° C.under a sustained H₂ pressure of 60 psi for 22 hours. The reaction iscooled to ambient temperature where it is repeatedly purged with N₂. Thecrude MeOH solution of(5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoicacid, methyl ester is carried on to subsequent steps withoutpurification, or optionally, it can be isolated via flash columnchromatography on silica gel, eluting with ethyl acetate-heptanemixtures. HPLC analysis (YMC ODS AQ S5; 1 mL/min; 30° C.; 254 nm:CH₃CN/H₂O, 60:40 (0-22 min.) to 100:0 (27-37 min.) to 60:40) indicated asyn:anti ratio of 1:1.4.

Chiral HPLC analysis (Chiralcel OD-H column; 5% EtOH:Hexanes;tR(3R,5R)=23.1 min./t_(R)(3R,5S)=18.0 min./t_(R)(3S,5S)=24.8min./t_(R)(3S,5R)=19.9 min.) indicated an enantiomeric excess at C-5 of≧97%, favoring the (R) configuration.

m/z (DCI(m+1)) 573; calcd for C₃₄H₃₇FN₂O₅ 572.27.

Step 7:5-(4-Fluorophenyl)-2-isoipropyl-1-[2-((S)-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide

A suitable nitrogen inerted reactor is charged with KOH (110.0 mmol) andwater (300 mL). To this rapidly stirring solution is added the crudeStep 6 solution of(5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoicacid, methyl ester (ca. 100 mmol/>98% ee) in MeOH (250 mL). The mixtureis heated under a nitrogen atmosphere to an internal temperature of ca.85° C. During this time, MeOH is removed via distillation. The resultingreaction mixture is allowed to cool to 45° C., where it is washed withMtBE (2×150 mL). The MtBE phases are separated and discarded. To the 45°C. aqueous phase is added toluene (125 mL), followed by a slow additionof 6N HCl (20 mL). The two-phase mixture is stirred for 10 minutes, andthe layers are separated. The aqueous phase is extracted with a secondportion of toluene (125 mL) and discarded. The combined organics areheated to reflux under a nitrogen atmosphere. During this time, 130 mLof distillate is collected and discarded. The resulting solution iscooled to ca. 60° C., where NEt₃ (140 mmol), DMAP (2.0 mmol) and Ac₂O(70.0 mmol) are added successively at such a rate as to maintain aninternal reaction temperature of 55° C. to 65° C. This solution isstirred for ca. 1.5 hrs at 60° C. The mixture is cooled to 50° C., where1N HCl (100 mL) is added slowly. The two-phase mixture is stirred for 10minutes, the phases are separated, and the aqueous phase discarded. Theorganic phase is washed with second portions of 1N HCl (100 mL) andwater (100 mL) while maintaining a temperature of 45° C. to 55° C. Thetoluene solution is diluted with Bu₂O (200 mL) and the resultingsolution is slowly cooled to 0° C. with continuous agitation. Theresulting solid is collected on a filter funnel and dried under vacuumto provide5-(4-fluorophenyl)-2-isopropyl-1-[2-((S)-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide as a white to off-white solid (34.4 g). This materialis carried on to subsequent steps without further purification, oroptionally, it can be re-precipitated from IPA/H₂O.

m/z (DCI(m+1)) 523; calcd for C₃₃H₃₁FN₂O₃ 522.23.

Chiral HPLC analysis (Chiralpak AD column; 1 ml/min; 30° C.; 254 nm; 10%IPA:Hexanes; tR(R)=18 min./tR(S)=16 min.) indicated an enantiomericexcess of >98%, favoring the (R) configuration.

Step 8:5-(4-Fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide

Method A

An argon-purged reactor is charged with5-(4-fluorophenyl)-2-isopropyl-1-[2-((S)-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide (0.020 mol/>99% ee) and benzyl alcohol (52 mL). Thereaction mixture is cooled to −10° C. and NaOH (0.040 mol) is added.After stirring for 19 hours at −10C the reaction is quenched with 37%HCl (0.042 mol) and diluted with water (25 mL) and toluene (25 mL).After the mixture is warmed to ambient temperature, the lower aqueouslayer is discarded. The upper organic layer is combined with 20%Pd(OH)₂/C (1.0 g) and H₂SO₄ (0.01 moles) and hydrogenated under 50 psihydrogen at 50° C. for 16 hours. The reaction mixture is heated to 80°C. and filtered through diatomaceous earth. The reactor and catalystcake is rinsed with hot toluene (10 mL). The lower aqueous layer isdiscarded. The upper organic layer is washed with a warm solution ofaqueous HCl (0.16 g 37% HCl in 25 mL hot water) and heated to reflux for2.5 hours under argon, removing water azeotropically. The reactionmixture is cooled to 65° C. and seeded with5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide. After 2 hours the reaction mixture is allowed toslowly cool to ambient temperature. The resulting slurry is cooled toabout 0° C. The product is collected and washed with cold toluene (25mL). The resulting solid is dissolved in hot toluene (95 mL) and cooledto 65° C. and held for 2 hours. The reaction mixture is slowly cooled toambient temperature and further cooled to 0° C. The product iscollected, washed with cold toluene (25 mL) and dried in vacuo at 70° C.overnight to afford5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide (8.4 g) as a white solid.

HPLC analysis (YMC ODS AQ S5; 1 mL/min; 30° C.; 254 nm: CH₃CN/H₂O, 60:40(0-22 min.) to 100:0 (27-37 min.) to 60:40) indicated an anti:syn ratioof >99:1.

Chiral HPLC analysis (Chiralcel OF; 1 mL/min; 60° C.; 254 nm; 20%

IPA:Hexanes; t_(R)(3R,5R)=26 min./t_(R)(3R,5S)=59 min./t_(R)(3S,5S)=33min./t_(R)(3S,5R)=37 min.) indicated an enantiomeric excess at C-5of >99%, favoring the (R) configuration.

m/z (DCI(m+1)) 541; calcd for C₃₃H₃₃FN₂O₄ 540.24.

In a process analogous to Step 8 METHOD A, substituted benzylic alcoholderivatives (e.g., p-methoxy-benzyl alcohol) may be used in place ofbenzyl alcohol to afford the corresponding compounds.Method B

An argon-purged reactor is charged with5-(4-fluorophenyl)-2-isopropyl-1-[2-((S)-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide (19.1 mmol/>99% ee) and allyl alcohol (50 mL). Thereaction mixture is cooled to −5° C. and LiOH (38.2 mmol) is added.After stirring for 1 hour at −5° C. the reaction is quenched with 37%HCl (42 mmol) and toluene (125 mL). After the mixture is warmed toambient temperature, the reaction is concentrated to a volume of ca. 75mL. Additional toluene (50 mL) is added and the reaction is concentratedvia distillation to a crude oil that solidifies upon standing. The cruderesidue is taken up in DME (340 mL). To this solution is added deionizedwater (20 mL), p-toluenesulfonic acid (2.25 g) and 5% Pd/C (11 g; 50%water-wet). The resulting mixture is heated to 45° C. under a N₂atmosphere for 1.5 hours and at ambient temperature for an additional 16hours. The solution is passed through filter aid to remove catalyst, andsolvent is removed in vacuo. The residue is taken up in toluene (50 mL).Water (75 mL) and KOH (950 mg) are added, and the reaction mixture isheated to 65° C. where the layers are separated. The aqueous phase iswashed with toluene (25 mL) at 65° C. and the combined toluene layersare discarded. To the aqueous phase is added toluene (50 mL), followedby 6N HCl (3.8 mL). The mixture is stirred vigorously at 65° C. for 5minutes and the phases are separated. The toluene phase is heated toreflux for 2.5 hours under argon, removing water azeotropically. Thereaction mixture is cooled to 65° C. and seeded with5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-H-pyrrole-3-carboxylicacid phenylamide. After 2 hours the reaction mixture is allowed toslowly cool to ambient temperature. The resulting slurry is cooled toabout 0° C. The product is collected and washed with cold toluene (25mL). The resulting solid is dissolved in hot toluene (95 mL) and cooledto 65° C. and held for 2 hours. The reaction mixture is slowly cooled toambient temperature and further cooled to 0° C. The product iscollected, washed with cold toluene (25 mL) and dried in vacuo at 70° C.overnight to afford5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide as a white solid.

HPLC analysis (YMC ODS AQ S5; 1 ml/min; 30° C.; 254 nm: CH₃CN/H₂O, 60:40(0-22 min) to 100:0 (27-37 min) to 60:40) indicated an anti:syn ratioof >99: 1.

Chiral HPLC analysis (ChiralCel OF; 1 mL/min; 60° C.; 254 nm; 20%IPA:Hexanes; tR(3R,5R)=26 min./tR(3R,5S)=59 min. tR(3S,SS)=33min./t_(R)(3S,5R)=37 min.) indicated an enantiomeric excess at C-5of >99%, favoring the (R) configuration.

m/z (DCI(m+1)) 541; calcd for C₃₃H₃₃FN₂O₄ 540.24.

In a process analogous to Step 8 METHOD B, allylic alcohol derivatives(e.g., crotyl alcohol) may be used in place of allyl alcohol to affordthe corresponding compounds.Method C

Operation A

A nitrogen inerted reactor is charged with(5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoicacid, tert-butyl ester (10.0 mmol), benzaldehyde dimethyl acetal (44.0mmol), toluene (40 mL) and p-toluenesulfonic acid monohydrate (1.0mmol). The reaction is stirred vigorously under vacuum for ca. 20 hours,or until complete reaction as determined by analysis of an aliquot byHPLC. The solution is cooled under a nitrogen atmosphere to ca.−5° C.where a IM THF solution of KOtBu (9.0 mmol) is added in three equalportions, separated by 30 to 45 minutes. The resulting solution isallowed to stir an additional 12 to 14 hours at 0° C. The reaction isquenched by the slow addition of 1N HCl (10 mL). The resulting two-phasemixture is allowed to warm to ca. 15° C. and is transferred to aseparatory funnel where the aqueous phase is removed and discarded. Theorganic phase is washed with saturated aqueous NaCl (100 mL), dried overanhydrous MgSO₄ (25 g), filtered and concentrated in vacuo to a crudeoil. This material is carried on to subsequent steps withoutpurification, or optionally, it can be re-precipitated fromether/hexanes.

m/z (APCI(m+1)) 703.4; calcd for C₄₄H₄₇FN₂O₅ 702.35.

In a process analogous to Step 8 METHOD C OPERATION A using theappropriate ester from Step 6 in place of(5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoicacid, tert-butyl ester, one obtains the following compounds, forexample:

-   ((4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-ethyl}-2-phenyl-[1,3]dioxan-4-yl)-acetic    acid methyl ester.-   ((4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-ethyl}-2-phenyl-[1,3]dioxan-4-yl)-acetic    acid ethyl ester.-   ((4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-ethyl}-2-phenyl-[1,3]dioxan-4-yl)-acetic    acid isopropyl, ester.    Operation B

A nitrogen inerted pressure reactor is charged with((4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-ethyl}-2-phenyl-[1,3]dioxan-4-yl)-aceticacid tert-butyl ester from OPERATION A (5.0 g), 5% Pd/C (0.45 g; 50%H₂O-wet), 2N HCl in MeOH (1.9 mL), toluene (11 mL), and MeOH (3.1 mL).The vessel and its contents are degassed via two cycles of partialevacuation and nitrogen pressurization (25 mm Hg and 50 psi,respectively). The atmosphere is switched to hydrogen via three cyclesof partial evacuation and hydrogen pressurization (25 mm Hg and 50 psi,respectively). The reaction is stirred vigorously at 40° C. under apositive pressure of H₂ (ca. 50 psi) for ca. 2.5 hours. The reaction isallowed to cool to ambient temperature, and the hydrogen pressure isreleased and replaced with nitrogen. The reaction is passed throughfiltering agent to remove the catalyst, rinsing thoroughly with MeOH(2×5 mL). To this solution is added KOH (0.6 g) in water (25 mL). Thereaction is stirred vigorously under a nitrogen atmosphere and heated toan internal reaction temperature of ca. 90° C., removing MeOH viadistillation. The two-phase mixture is allowed to cool to 70° C. and theupper toluene phase is separated and discarded. The aqueous phase iswashed with a second portion of toluene (10 mL) at 70° C. This organicwash is also separated and discarded. To the aqueous phase is addedtoluene (10 mL), followed by a slow addition of 2N HCl (5 mL). Thetwo-phase mixture is stirred for 10 minutes and the layers areseparated. The aqueous phase is extracted with a second portion oftoluene (10 mL) and is discarded. The combined organics are heated toreflux under a Dean-Stark water trap for 2.5 hours under argon. Thereaction mixture is cooled to 65° C. and seeded with5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide. After 2 hours the reaction mixture is allowed toslowly cool to ambient temperature. The resulting slurry is cooled toca. 0° C. The product is collected and washed with cold toluene (5 mL).The resulting solid is dissolved in hot toluene (20 mL) and cooled to65° C. and held for 2 hours. The reaction mixture is slowly cooled toambient temperature and then to 0° C. The product is collected, washedwith cold toluene (5 μL) and dried in vacuo at 70° C. overnight toafford5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide as a white solid.

m/z (DCI(m+1)) 541; calcd for C₃₃H₃₃FN₂O₄ 540.24.Method D

A nitrogen inerted pressure reactor is charged with7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoicacid, ethyl ester (100.0 mmol) and EtOH (250 μL). The resulting slurryis heated with stirring to ca. 55° C. to afford a homogeneous solution.The vessel and its contents are degassed via three 50 psi pressurepurges with argon. Under a steady flow of argon, 1 M ethanolic HBr (7.0mmol) and the RuCl₂([(R)-BINAP] NEt₃ catalyst (0.5 mmol) are added, andthe reactor is given an additional 50 psi pressure purge with argon. Theatmosphere is switched to hydrogen via three 50 psi pressure purges. Thereaction is stirred vigorously at 65° C. under a sustained pressure ofhydrogen (50 psi) until H₂ uptake ceases. The reaction is allowed tocool to ca. 50° C., where the hydrogen pressure is released and replacedwith nitrogen. The crude EtOH solution of(5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoicacid, methyl ester is diluted with toluene (250 mL). To this solution isadded benzaldehyde (150 mmol) and p-TsOH monohydrate (5 mmol). Theresulting reaction mixture is heated to a pot temperature of 110° C.,removing EtOH and water via their toluene azeotropes. The solution iscooled under a nitrogen atmosphere to ca.−5° C. where a 1 M THF solutionof KOtBu (90 mmol) is added in three equal portions, separated by 30 to45 minutes. The resulting solution is allowed to stir an additional 12to 14 hours at 0° C. The reaction is quenched by the slow addition of 1NHCl (100 mL). The resulting two-phase mixture is allowed to warm to ca.15° C. and is transferred to a separatory funnel where the aqueous phaseis removed and discarded. The organic phase is washed with saturatedaqueous NaCl (25 mL), dried over anhydrous MgSO₄ (5 g), filtered andconcentrated in vacuo to a crude oil that is taken up in MeOH (200 mL).This solution is transferred to a nitrogen inerted pressure reactorcontaining 5% Pd/C (5 g; 50% water-wet). Concentrated HCl (2 mL) isadded and the reaction is stirred under a sustained pressure of H₂ (50psi) for ca. 3 hours at 50° C. The reaction mixture is cooled to ambienttemperature, the H₂ is replaced by N₂, and the catalyst is removed viafiltration. This solution of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoicacid, methyl ester is transferred to a nitrogen inerted reactor chargedwith KOH (110.0 mmol) and water (300 mL). The mixture is heated under anitrogen atmosphere to an internal temperature of ca. 85° C. During thistime, MeOH is removed via distillation. The resulting reaction mixtureis allowed to cool to 45° C., where it is washed with MtBE (2×150 mL).The MtBE phases are separated and discarded. To the 45° C. aqueous phaseis added toluene (125 mL), followed by a slow addition of 6N HCl (20mL). The two-phase mixture is stirred for 10 minutes and the layers areseparated. The aqueous phase is extracted with a second portion oftoluene (125 mL) and is discarded. The combined organics are heated toreflux under a Dean-Stark water trap for 2.5 hours under argon. Thereaction mixture is cooled to 65° C. and seeded with5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide. After 2 hours the reaction mixture is allowed toslowly cool to ambient temperature. The resulting slurry is cooled toca. 0° C. The product is collected and washed with cold toluene (100mL). The resulting solid is dissolved in hot toluene (350 mL) and cooledto 65° C. where it is held for 2 hours. The reaction mixture is slowlycooled to ambient temperature and then to 0° C. The product iscollected, washed with cold toluene (100 ML) and dried in vacuo at 70°C. to afford5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide as a white solid.

m/z (DCI(m+1)) 541; calcd for C₃₃H₃₃FN₂O₄ 540.24.

Step 9:(R,R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoicacid, calcium salt

An argon-purged reactor is charged with5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide (14.8 mmol), MtBE (45 mL) and MeOH (20 mL). A solutionof NaOH (15.2 mmol) in water (103 mL) is added and the reaction mixtureheated to 52° C. After heating for ca. 1 hour, the reaction mixture iscooled to 34° C. and the layers are allowed to separate. The upperorganic layer is discarded. The lower aqueous layer is washed with MtBE(33 mL) at ca. 33° C. The lower aqueous layer is diluted with MtBE (2mL) and heated to 52° C. under argon. A warm solution of Ca(OAc)₂.H₂O(7.5 mmol) in water (44 mL) is added over ca. 2 hours. About 5 minutesafter the start of the Ca(OAc)₂ addition, the reaction mixture is seededwith a slurry of(R,R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoicacid, calcium salt (0.08 mmol) in water (1.2 mL) and methanol (0.4 mL).After the Ca(OAc)₂ addition is complete, the reaction mixture is heldfor ca. 15 minutes at 52° C. and cooled to 20° C. The product iscollected, washed sequentially with a 2:1 solution of aqueous methanol(48 mL) and water (49 mL). After drying in vacuo at 70° C.,(R,R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoicacid, calcium salt (8.7 g) is obtained as a white solid. The analyticalspecifications of this material are in agreement with the valuesreported in the prior art.

Preparation of Catalysts

EXAMPLE A RuCl?(DMF)_(n)[(R)-(+)-Cl—MeO-BIPHEP1 complex

A suitable reaction flask is charged with DMF (17.5 nL). The vessel andits contents are degassed via two cycles of partial evacuation andnitrogen pressurization (25 mm Hg and 10 psi, respectively). The excessnitrogen pressure is released, and benzene ruthenium(II) chloride dimer(0.50 mmol) and (R)-(+)-Cl—MeO-BIPHEP (1.10 mmol) are added in rapidsuccession. The vessel and its contents are again degassed via twocycles of partial evacuation and nitrogen pressurization (25 mm Hg and10 psi, respectively). The excess nitrogen pressure is released, and thereactor is heated to ca. 100° C. for 10 minutes. The resulting solutionis allowed to cool to <50° C. where solvent is removed in vacuo,affording RuCl2(DMF)_(n)[(R)-(+)-Cl—MeO-BIPHEP] as a rusty-brown solid.The crude complex is used directly in subsequent reactions withoutpurification or unambiguous characterization, or optionally, can bestored under an inert atmosphere for future use.

In a process analogous to EXAMPLE A using the appropriate chiraldiphosphine ligand in place of (R)-(+)-Cl—MeO-BIPHEP, the followingcomplexes can be obtained, for example:

-   -   RuCl₂(DMF)_(n)[(R)-(+)-BINAP]_(n) complex.    -   RuCl2(DMF)_(n)[(R)-(+)-pTol-BINAP]_(n) complex.    -   RuCl₂(DMF)_(n)[(R)-(+)—C4-TunaPhos]_(n) complex.    -   RuCl₂(DMF)_(n)[(R)-(+)—C2-TunaPhos]_(n) complex.    -   RuCl₂(DMF)_(n)[(S)-(−)-MeO-BIPHEP]_(n) complex.

EXAMPLE B RuCl₂[(R)-(+)-BINAP] (NEt3 n complex

A nitrogen inerted pressure reactor is charged withdichloro-(1,5-cyclooctadiene)-ruthenium (II) dimer (0.15 mmol) and(R)-(+)-BINAP (0.32 mmol). Toluene (8.0 mL) is added, followed bytriethylamine (4.5 mmol). The vessel and its contents are degassed viatwo cycles of partial evacuation and nitrogen pressurization (25 mm Hgand 10 psi, respectively). The excess nitrogen pressure is released, andthe reactor is sealed and heated to ca. 140° C. where it is maintainedfor ca. 4 hours. The resulting clear red solution is allowed to cool to≦40° C. where solvent is removed in vacuo, affordingRuCl₂[(R)-(+)-BINAP] (NEt3)_(n) complex as a rusty-brown solid. Thecrude complex is used directly in subsequent reactions withoutpurification or unambiguous characterization, or optionally, can bestored under an inert atmosphere for future use.

In a process analogous to EXAMPLE B using the appropriate chiraldiphosphine ligand in place of (R)-(+)-BINAP, the following complexescan be obtained, for example:

-   -   RuCl₂[(R)-(+)-Cl—MeO-BIPHEP] (NEt3)_(n) complex.    -   RuCl₂[(R)-(+)-BINAP] (NEt3)_(n) complex.    -   RuCl₂[(R)-(+)-pTol-BINAP] (NEt3)_(n) complex.

EXAMPLE C [Ru(TFA)₂((R)-(+)-Cl—MeO-BIPHEP)]_(n) complex

A suitable reaction flask is charged with acetone (50 mL). The vesseland its contents are degassed via two cycles of partial evacuation andargon pressurization (25 mm Hg and 10 psi, respectively). The excessargon pressure is released, and (0.50 mmol) and (R)-(+)-Cl—MeO-BIPHEP(0.51 mmol) are added in rapid succession. The vessel and its contentsare again degassed via two cycles of partial evacuation and argonpressurization (25 mm Hg and 10 psi, respectively). The excess argonpressure is released, and the reactor is stirred vigorously at ca. 30°C. Trifluoroacetic acid (1.2 mmol) is added via syringe and the reactionmixture is stirred for an additional 1-hour period. Solvent is removedin vacuo, with careful omission of O₂, to afford[Ru(TFA)₂((R)-(+)-Cl—MeO-BIPHEP)]_(n) complex as a solid. The crudecomplex is used directly in subsequent reactions without purification orunambiguous characterization, or optionally, can be stored under aninert atmosphere for future use.

In a process analogous to EXAMPLE C using the appropriate chiraldiphosphine ligand in place of (R)-(+)-Cl—MeO-BIPHEP, the followingcomplexes can be obtained, for example:

-   -   [Ru(TFA)₂((R)-(+)-MeO-BIPHEP)]_(n) complex.    -   [Ru(TFA)₂((R)-(+)-BINAP)]_(n) complex.    -   [Ru(TFA)₂((R)-(+)-pTol-BINAP)]_(n) complex.

1. A process for the preparation of a compound of Formula (13)

which comprises: Step (a) reacting a compound of Formula (1)

wherein R is alkyl, aryl, arylalkyl, or heteroaryl in a solvent with acompound of Formula (2)R¹—H  (2) wherein R¹ is —XR wherein X is O, S, or Se, or R¹ is

wherein R² or R³ is independently alkyl, cycloalkyl, arylalkyl, or aryl,or R² and R³ together are —(CH₂)₄—, —(CH₂)₅—, —(CH(R⁴)—CH₂)₃—,—(CH(R⁴)—CH₂)₄—, —(CH(R⁴)—(CH₂)₂—CH(R⁴))—, —(CH(R⁴)—(CH₂)₃—CH(R⁴))—,—CH₂—CH₂-A-CH₂—CH₂—, —CH(R⁴)—CH₂-A-CH₂CH₂—, —CH(R⁴)—CH₂-A-CH₂—CH(R⁴)—wherein R⁴ is alkyl of from one to four carbon atoms, A is O, S, or N,and R is as defined above to afford a compound of Formula (3)

wherein R¹ is as defined above; Step (b) reacting a compound of Formula(3) with hydrogen in the presence of a catalyst and a strong acid in asolvent to afford a compound of Formula (4)

wherein Y is Cl, Br, TsO, MsO, or HSO₄, and R¹ is as defined above; Step(c) reacting a compound of Formula (4) with a base in a solvent followedby the addition of a compound of Formula (5)R—CO₂H  (5) wherein R is as defined above in a solvent to afford acompound of Formula (6)

wherein R and R¹ are as defined above; Step (d) reacting a compound ofFormula (6) with Compound (7)

in a solvent with removal of water to afford a compound of Formula (8)

wherein R¹ is as defined above; Step (e) reacting a compound of Formula(8) with a compound of Formula (9)

wherein M is sodium, lithium, potassium, zinc, magnesium, copper,calcium, or aluminum, and R¹ is as defined above in a solvent in thepresence of a strong base to afford a compound of Formula (10)

wherein R¹ is as defined above; Step (f) reacting a compound of Formula(10) with hydrogen in the presence of a catalyst in a solvent in thepresence of an acid to afford a compound of Formula (11)

wherein R¹ is as defined above or a compound of Formula (11a)

Step (g) reacting a compound of Formula (11b)

wherein R¹a is OH, XR wherein X is O, S, or Se, or R^(1a) is

wherein R² or R³ is independently alkyl, cycloalkyl, arylalkyl, or aryl,or R² and R³ together are —(CH₂)₄—, —(CH₂)₅—, —(CH(R⁴)—CH₂)₃—,—(CH(R⁴)—CH₂)₄—, —(CH(R⁴)—(CH₂)₂—CH(R⁴))—, —(CH(R⁴)—(CH₂)₃—CH(R⁴))—,—CH₂—CH₂-A-CH₂—CH₂—, —CH(R⁴)—CH₂-A-CH₂CH₂—, —CH(R⁴)—CH₂-A-CH₂—CH(R⁴)—wherein R⁴ is alkyl of from one to four carbon atoms, A is O, S, or Nand R is alkyl, aryl, arylalkyl, or heteroaryl in a solvent in thepresence of an acid, followed by reaction with a base, an acylatingagent, and an acylation catalyst in a solvent to afford a compound ofFormula (12)

Step (h) reacting a compound of Formula (12) with HO-M in an alcohol ofFormula (17) or (17b)HOCH₂-Aryl  (17)or HO-Allyl  (17b) wherein M is sodium, lithium, potassium, zinc,magnesium, copper, calcium, or aluminum, or with a compound of Formula(16) or (16b)M^({circle over (+)} {circle over (−)}) OCH₂-Aryl  (16)or M^({circle over (+)} {circle over (−)}) O-Allyl  (16b) wherein M isas defined above in an alcohol of Formula (17) or (17b) wherein aryl orallyl in a compound of Formula (16) or (16b) and (17) or (17b) is thesame, in a solvent followed by the addition of hydrogen in the presenceof a catalyst and an acid to afford the compound of Formula (13).
 2. Theprocess according to claim 1, wherein the solvent in Step (a) is methyltertiary butyl ether.
 3. The process according to claim 1, wherein thecatalyst in Step (b) is selected from the group consisting of Pt/C,Pd/C, Sponge Ni and a metal hydride.
 4. The process according to claim3, wherein the catalyst is Pt/C.
 5. The process according to claim 1,wherein the solvent in Step (b) is selected from the group consisting ofmethanol and ethanol.
 6. The process according to claim 5, wherein thesolvent is methanol.
 7. The process according to claim 1, wherein theacid in Step (c) is selected from the group consisting of an alkylcarboxylic acid or an aryl carboxylic acid.
 8. The process according toclaim 7, wherein the acid is selected from the group consisting ofacetic acid, propionic acid, butyric acid, pivalic acid, benzoic acid,and phenylacetic acid.
 9. The process according to claim 8, wherein theacid is phenylacetic acid.
 10. The process according to claim 1, whereinthe solvent in Step (c) is selected from the group consisting of analcohol, toluene, methyl tertiary butyl ether, and tetrahydrofuran. 11.The process according to claim 10, wherein the solvent is methanol, ormethyl tertiary butyl ether.
 12. The process according to claim 1,wherein the solvent in Step (d) is selected from the group consisting ofa protic solvent, an aprotic solvent, a polar solvent, and a non polarsolvent.
 13. The process according to claim 12, wherein the solvent istetrahydrofuran.
 14. The process according to claim 1, wherein thesolvent in Step (e) is a nonreactive aprotic solvent.
 15. The processaccording to claim 14, wherein the solvent is tetrahydrofuran.
 16. Theprocess according to claim 1, wherein the strong base in Step (e) isselected from the group consisting of an alkyl lithium, lithiumhexamethyldisilazide, potassium hexamethyldisilazide, and lithiumdiisopropylamide.
 17. The process according to claim 16, wherein thebase is n-butyllithium.
 18. The process according to claim 1, whereinthe catalyst in Step (f) is a ruthenium catalyst precursor and a chiralnon-racemic diphosphine ligand.
 19. The process according to claim 18,wherein the ruthenium catalyst precursor is selected from the groupconsisting of dichloro-(1,5-cyclooctadiene)-ruthenium (II) oligomer,dibromo-(1,5-cycloocctadiene)-ruthenium (II) dimer,[bis-(2-methallyl)cycloocta-1,5-diene] ruthenium (II) complex anddichloro (p-cymene) ruthenium (II) dimer.
 20. The process according toclaim 18, wherein the chiral diphosphine ligand is selected from thegroup consisting of 2,2′-bis(di-p-tolyl-phosphino)-1,1′-binaphthyl,2-diphenyl-phosphinomethyl-4-diphenylphosphino-1-tert-butoxy-carbonylpyrrolidine,tricyclo[8.2.2.24,7]hexadeca-4,6,10,12,13,15-hexaene-5,11-diyl-bis(diphenylphosphine)derivatives, 4,4′-bidibenzofuran-3,3′-diylbis(diphenylphosphine),6,6′-dimethoxy[1,1′-biphenyl]-2,2′-diyl]bis-diphenylphosphine,[5,5′-dichloro-6,6′-dimethoxy[1,1′-biphenyl]-2,2′-diyl]-bis-diphenylphosphine,[6,7-dihydrodibenzo[e,g] [1,4]dioxocin-1,12-diyl]-bis-diphenylphosphine,and 1,2-bis(2,5-dimethylphospholano)benzene derivatives.
 21. The processaccording to claim 18, wherein the catalyst is RuCl₂ (DMF)_(n)((R)-(+)-Cl—MeO-BIPHEP).
 22. The process according to claim 1, whereinthe solvent in Step (f) is selected from the group consisting of analcohol, dichloromethane, tetrahydrofuran, and toluene.
 23. The processaccording to claim 22, wherein the alcohol is selected from the groupconsisting of methanol, ethanol, and isopropanol.
 24. The processaccording to claim 23, wherein the alcohol is methanol.
 25. The processaccording to claim 1, wherein the acid in Step (f) is selected from thegroup consisting of hydrochloric acid, hydrobromic acid, and acidicDowex ion exchange resin.
 26. The process according to claim 1, whereinthe solvent in Step (g) is selected from the group consisting oftoluene, dichloromethane, and methyl-tert butyl ether.
 27. The processaccording to claim 26, wherein the solvent is toluene.
 28. The processaccording to claim 1, wherein the acid in Step (g) is selected from thegroup consisting of hydrogen chloride, sulfuric acid,para-toluenesulfonic acid, and camphorsulfonic acid.
 29. The processaccording to claim 28, wherein the acid is para-toluenesulfonic acid.30. The process according to claim 1, wherein the base in Step (g) isselected from the group consisting of triethylamine,N,N-diisopropylethylamine, and pyridine.
 31. The process according toclaim 30, wherein the base is triethylamine.
 32. The process accordingto claim 1, wherein the acylating agent in Step (g) is selected from thegroup consisting of acetic anhydride, benzoyl chloride, and benzylchloroformate.
 33. The process according to claim 32, wherein theacylating agent is acetic anhydride.
 34. The process according to claim1, wherein the solvent in Step (h) is selected from the group consistingof acetone, 1,2-dimethoxyethane, and tetrahydrofuran.
 35. The processaccording to claim 34, wherein the solvent is tetrahydrofuran.
 36. Theprocess according to claim 1 wherein M is Step (h) is selected from thegroup consisting of potassium, sodium, and lithium.
 37. The processaccording to claim 36 wherein M is sodium.
 38. The process according toclaim 1 wherein the acid is Step (h) is selected from the groupconsisting of hydrochloric acid, hydrobromic acid, and sulfuric acid.39. The process according to Step 38 wherein the acid is sulfuric acid.40. The process according to claim 1, wherein the catalyst in Step (h)is selected from the group consisting of Pd(OH)₂/C, Pd/C, and Pd/Al₂O₃.41. The process according to claim 40, wherein the catalyst isPd(OH)₂/C.
 42. The process according to claim 1, wherein R is methyl orethyl in a compound of Formula (1).
 43. The process according to claim1, wherein the compound of Formula (2) is morpholine.
 44. The processaccording to claim 1, wherein the compound of Formula (3) is


45. The process according to claim 1, wherein the compound of Formula(4) is


46. The process according to claim 1, wherein the compound of Formula(5) is phenylacetic acid.
 47. The process according to claim 1, whereinthe compound of Formula (6) is


48. The process according to claim 1, wherein R¹ in a compound ofFormula (8) is


49. The process according to claim 1, wherein M is selected from thegroup consisting of sodium, lithium, and potassium, and R¹ is selectedfrom the group consisting of —O-methyl, —O-ethyl, and —O-tert-butyl in acompound of Formula (9).
 50. The process according to claim 1, whereinR¹ is —O-methyl, —O-ethyl, and —O-tert-butyl in a compound of Formula(10).
 51. The process according to claim 1, wherein R¹ is —O-methyl,—O-ethyl, and —O-tert-butyl in a compound of Formula (11b).
 52. Aprocess for the preparation of a compound of Formula (8)

wherein R¹ is —XR wherein X is O, S, or Se, or R¹ is

wherein R² or R³ is independently alkyl, cycloalkyl, arylalkyl, or aryl,or R² and R³ together are —(CH₂)₄—, —(CH₂)₅—, —(CH(R⁴)—CH₂)₃—,—(CH(R⁴)—CH₂)₄—, —(CH(R⁴)—(CH₂)₂—CH(R⁴))—, —(CH(R⁴)—(CH₂)₃—CH(R⁴))—,—CH₂—CH₂-A-CH₂—CH₂—, —CH(R⁴)—CH₂-A-CH₂CH₂—, —CH(R⁴)—CH₂-A-CH₂—CH(R⁴)—wherein R⁴ is alkyl of from one to four carbon atoms, A is O, S, or N,and R is alkyl, aryl, arylalkyl, or heteroaryl which comprises: reactinga compound of Formula (4)

wherein Y is Cl, Br, TsO, MsO, or HSO₄, and R¹ is as defined above witha compound of Formula (20)R—CO₂ ^({circle over (−)} {circle over (+)}) M  (20) wherein R is asdefined above and M is sodium, lithium, potassium, zinc, magnesium,copper, calcium, or aluminum with Compound (7)

in a solvent with removal of water to afford a compound of Formula (8).53. A process for the preparation of compound (13)

which compris es: Step (a) reacting a compound of Formula (11)

wherein R¹ is —XR wherein X is O, S, or Se, or R¹ is

wherein R² or R³ is independently alkyl, cycloalkyl, arylalkyl, or aryl,or R² and R³ together are —(CH₂)₄—, —(CH₂)₅—, —(CH(R⁴)—CH₂)₃—,—(CH(R⁴)—CH₂)₄—, —(CH(R⁴)—(CH₂)₂—CH(R⁴))—, —(CH(R⁴)—(CH₂)₃—CH(R⁴))—,—CH₂—CH₂-A-CH₂—CH₂—, —CH(R⁴)—CH₂-A-CH₂CH₂—, —CH(R⁴)—CH₂-A-CH₂—CH(R⁴)—wherein R⁴ is alkyl of from one to four carbon atoms, A is O, S, or N,and R is alkyl, aryl, arylalkyl, or heteroaryl with an acetal of Formula(15)

wherein R⁵ and R⁵a are independently the same or different and aremethyl, ethyl or —(CH₂)_(n)— wherein n is an integer of 2 to 4, and R isas defined above in a solvent in the presence of an acid followed by theaddition of an aldehyde corresponding to the previous acetal in thepresence of a base to afford a compound of Formula (14)

wherein R¹ and R are as defined above; Step (b) reacting a compound ofFormula (14) in a solvent in the presence of an acid or optionallyreaction with hydrogen in the presence of a catalyst and an acid in asolvent to afford the compound of Formula (13); and Step (c)alternatively, reacting a compound of Formula (11) or (11a) in a

solvent in the presence of an acid to afford a compound of Formula (13).54. The process according to claim 53, wherein the acid in Step (a) isselected from the group consisting of hydrogen chloride,para-toluenesulfonic acid and pyridinium para-toluenesulfonate.
 55. Theprocess according to claim 54, wherein the acid is para-toluenesulfonicacid.
 56. The process according to claim 53, wherein the acetal in Step(a) is benzaldehyde dimethyl acetal.
 57. The process according to claim53, wherein the base in Step (a) is a non-nucleophilic strong base. 58.The process according to claim 53, wherein the base is selected from thegroup consisting of potassium tert butoxide, potassium bis(trimethylsilyl) amide, and 1,-8-diazabicyclo[5.4.0.]undec-7-ene. 59.The process according to claim 58, wherein the base is potassiumtertiary butoxide.
 60. The process according to claim 53, wherein thesolvent in Step (b) is selected from the group consisting of toluene,dichloromethane, and methyl tertiary butyl ether.
 61. The processaccording to claim 60, wherein the solvent is toluene.
 62. The processaccording to claim 53, wherein the acid in Step (b) is selected from thegroup consisting of hydrogen chloride, pyridinium para-toluenesulfonateand para-toluenesulfonic acid.
 63. The process according to claim 62,wherein the acid is para-toluenesulfonic acid.
 64. The process accordingto claim 53, wherein the catalyst in Step (b) is selected from the groupconsisting of palladium on carbon, and platinum on carbon, in thepresence of hydrochloric acid.
 65. The process according to claim 53,wherein the solvent in Step (c) is selected from the group consisting oftoluene, dichloromethane, acetonitrile, and methyl tertiary butyl ether.66. The process according to claim 65, wherein the solvent is toluene.67. The process according to claim 53, wherein the acid in Step (c) isselected from the group consisting of hydrochloric acid, sulfuric acid,pyridinium p-toluenesulfonate, and para-toluenesulfonic acid.
 68. Theprocess according to claim 67, wherein the acid is para-toluenesulfonicacid.
 69. The process according to claim 53, wherein R¹ is selected fromthe group consisting of —O-methyl, —O-ethyl, and —O-tert butyl in acompound of Formula (11).
 70. The process according to claim 53, whereinR¹ is selected from the group consisting of —O-methyl, —O-ethyl, and—O-tert butyl in a compound of Formula (14).
 71. A process for thepreparation of a compound of Formula (11b)

wherein R¹a is OH, —XR wherein X is O, S, Se, or R^(1a) is

wherein R² or R³ is independently alkyl, cycloalkyl, arylalkyl, or aryl,or R² and R³ together are —(CH₂)₄—, —(CH₂)₅—, —(CH(R⁴)—CH₂)₃—,—(CH(R⁴)—CH₂)₄—, —(CH(R⁴)—(CH₂)₂—CH(R⁴))—, —(CH(R⁴)—(CH₂)₃—CH(R⁴))—,—CH₂—CH₂-A-CH₂—CH₂—, —CH(R⁴)—CH₂-A-CH₂CH₂—, —CH(R⁴)—CH₂-A-CH₂—CH(R⁴)—wherein R⁴ is alkyl of from one to four carbon atoms, A is O, S, or N,and R is alkyl, aryl, arylalkyl, or heteroaryl which comprises: Step (a)reacting a compound of Formula (10)

wherein R¹ is XR or R¹ is

wherein X, R, R², and R³ are as defined above with one mole of hydrogenin the presence of a catalyst in a solvent in the presence of an acid toafford compounds of Formula (18) and/or Formula (18a)

wherein R¹ is as defined above; and Step (b) reacting either a compoundof Formula (18) or (18a) with hydrogen in the presence of a catalyst ina solvent in the presence of an acid to afford a compound of Formula(11b).
 72. The process according to claim 71 wherein the catalyst inStep (a) or (b) is a ruthenium catalyst precursor and a chiralnon-racemic diphosphine ligand.
 73. The process according to claim 72,wherein the ruthenium catalyst precursor is selected from the groupconsisting of dichloro-(1,5-cyclooctadiene)-ruthenium (II) oligomer,dibromo-(1,5-cyclooctadiene)-ruthenium (II) dimer,[bis-(2-methallyl)cycloocta-1,5-diene] ruthenium (II) complex anddichloro (p-cymene) ruthenium (II) dimer.
 74. The process according toclaim 72, wherein the chiral diphosphine ligand is selected from thegroup consisting of 2,2′-bis(di-p-tolyl-phosphino)-1,1′-binaphthyl,2-diphenyl-phosphinomethyl-4-diphenylphosphino-1-tert-butoxy-carbonylpyrrolidine,tricyclo[8.2.2.24,7]hexadeca-4,6,10,12,13,15-hexaene-5,11-diyl-bis(diphenylphosphine)derivatives, 4,4′-bidibenzofuran-3,3′-diylbis(diphenylphosphine),6,6′-dimethoxy[1,1′-biphenyl]-2,2′-diyl]bis-diphenylphosphine,[5,5′-dichloro-6,6′-dimethoxy[1,1′-biphenyl]-2,2′-diyl]-bis-diphenylphosphine,[6,7-dihydrodibenzo[e,g] [1,4]dioxocin-1,12-diyl]-bis-diphenylphosphine,and 1,2-bis(2,5-dimethylphospholano)benzene derivatives.
 75. The processaccording to claim 72, wherein the catalyst is RuCl₂ (DMF)_(n)((R)-(+)-Cl—MeO-BIPHEP).
 76. The process according to claim 71, whereinthe solvent in Step (a) or (b) is selected from the group consisting ofan alcohol, dichloromethane, tetrahydrofuran, and toluene.
 77. Theprocess according to claim 76, wherein the alcohol is selected from thegroup consisting of methanol, ethanol, and isopropanol.
 78. The processaccording to claim 76, wherein the alcohol is methanol.
 79. A processaccording to claim 71 wherein the acid in Step (a) or (b) is hydrobromicacid.
 80. A compound of Formula (6)

wherein R is alkyl, aryl, arylalkyl, or heteroaryl, and wherein R¹ is—XR wherein X is O, S, or Se, or R¹ is

wherein R² or R³ is independently alkyl, cycloalkyl, arylalkyl, or aryl,or R² and R³ together are —(CH₂)₄—, —(CH₂)₅—, —(CH(R⁴)—CH₂)₃—,—(CH(R⁴)—CH₂)₄—, —(CH(R⁴)—(CH₂)₂—CH(R⁴))—, —(CH(R⁴)—(CH₂)₃—CH(R⁴))—,—CH₂—CH₂-A-CH₂—CH₂—, —CH(R⁴)—CH₂-A-CH₂CH₂—, —CH(R⁴)—CH₂-A-CH₂—CH(R⁴)—wherein R⁴ is alkyl of from one to four carbon atoms, A is O, S, or N,and R is as defined above.
 81. The compound according to claim 80,wherein R is PhCH₂— or (CH₃)₃—C—, and R¹ is


82. The compound according to claim 80, which is


83. A compound of Formula (8)

wherein R¹ is —XR wherein X is O, S, or Se, or R¹ is

wherein R² or R³ is independently alkyl, cycloalkyl, arylalkyl, or arylor R² and R³ together are —(CH₂)₄—, —(CH₂)₅—, —(CH(R⁴)—CH₂)₃—,—(CH(R⁴)—CH₂)₄—, —(CH(R⁴)—(CH₂)₂—CH(R⁴))—, —(CH(R⁴)—(CH₂)₃—CH(R⁴))—,—CH₂—CH₂-A-CH₂—CH₂—, —CH(R⁴)—CH₂-A-CH₂CH₂—, —CH(R⁴)—CH₂-A-CH₂—CH(R⁴)—wherein R⁴ is alkyl of from one to four carbon atoms, A is O, S, or N,and R is alkyl, aryl, arylalkyl, or heteroaryl.
 84. The compoundaccording to claim 83, wherein R¹ is


85. A compound of Formula (10) or a pharmaceutically acceptable saltthereof

wherein R¹—XR wherein X is O, S, or Se, or R¹ is

wherein R² or R³ is independently alkyl, cycloalkyl, arylalkyl, or arylor R² and R³ together are —(CH₂)₄—, —(CH₂)₅—, —(CH(R⁴)—CH₂)₃—,—(CH(R⁴)—CH₂)₄—, —(CH(R⁴)—(CH₂)₂—CH(R⁴))—, —(CH(R⁴)—(CH₂)₃—CH(R⁴))—,—CH₂—CH₂-A-CH₂—CH₂—, —CH(R⁴)—CH₂-A-CH₂CH₂—, —CH(R⁴)—CH₂-A-CH₂—CH(R⁴)—wherein R⁴ is alkyl of from one to four carbon atoms, A is O, S, or N,and R is alkyl, aryl, arylalkyl, or heteroaryl.
 86. The compoundaccording to claim 85, wherein R¹ is —O-tertiary butyl, —O-isopropyl,—O-ethyl, —O-methyl,

or —NMe₂.
 87. A compound of Formula (12)


88. A compound of Formula (18) or a pharmaceutically acceptable saltthereof

wherein R¹ is —XR wherein X is O, S, or Se, or R¹ is

wherein R² or R³ is independently alkyl, cycloalkyl, arylalkyl, or arylor R² and R³ together are —(CH₂)₄—, —(CH₂)₅—, —(CH(R⁴)—CH₂)₃—,—(CH(R⁴)—CH₂)₄—, —(CH(R⁴)—(CH₂)₂—CH(R⁴))—, —(CH(R⁴)—(CH₂)₃—CH(R⁴))—,—CH₂—CH₂-A-CH₂—CH₂—, —CH(R⁴)—CH₂-A-CH₂CH₂—, —CH(R⁴)—CH₂-A-CH₂—CH(R⁴)—wherein R⁴ is alkyl of from one to four carbon atoms, A is O, S, or N,and R is alkyl, aryl, arylalkyl, or heteroaryl.
 89. The compoundaccording to claim 88 wherein R¹ is —O-tertiary butyl, —O-isopropyl,—O-ethyl, —O-methyl,

or —NMe₂.
 90. A compound of Formula (18a) or a pharmaceuticallyacceptable salt thereof

wherein R¹ is —XR wherein X is O, S, or Se, or R¹ is

wherein R² or R³ is independently alkyl, cycloalkyl, arylalkyl, or arylor R² and R³ together are —(CH₂)₄—, —(CH₂)₅—, —(CH(R⁴)—CH₂)₃—,—(CH(R⁴)—CH₂)₄—, —(CH(R⁴)—(CH₂)₂—CH(R⁴))—, —(CH(R⁴)—(CH₂)₃—CH(R⁴))—,—CH₂—CH₂-A-CH₂—CH₂—, —CH(R⁴)—CH₂-A-CH₂CH₂—, —CH(R⁴)—CH₂-A-CH₂—CH(R⁴)—wherein R⁴ is alkyl of from one to four carbon atoms, A is O, S, or N,and R is alkyl, aryl, arylalkyl, or heteroaryl.
 91. The compoundaccording to claim 90, wherein R¹ is —O-tertiary butyl, —O-isopropyl,—O-ethyl, —O-methyl,

or —NMe₂.